bims-merabr 2024-05-05 papers

bims-merabr

Biomed News

on Metabolic rewiring in aggressive breast cancer

Issue of 2024‒05‒05
34 papers selected by
Barbara Mensah Sankofi, University of Oklahoma Health Sciences Center

Targeting metabolism of breast cancer and its implications in T cell immunotherapy.
Diet modulates the gut microbiome, metabolism, and mammary gland inflammation to influence breast cancer risk.
Why does hormonal contraception and menopausal hormonal treatment have such a small effect on breast cancer risk?
Triclocarban and triclosan promote breast cancer progression in vitro and in vivo via activating G protein-coupled estrogen receptor signaling pathways.
Expression and Significance of LINC02418 in Breast Cancer.
Impaired Fibroblast Growth Factor 21 (FGF21) Associated with Visceral Adiposity Leads to Insulin Resistance: The Core Defect in Diabetes Mellitus.
MiR-103a-3p Promotes Tumorigenesis of Breast Cancer by Targeting ETNK1.
MCT4 knockdown by tumor microenvironment-responsive nanoparticles remodels the cytokine profile and eradicates aggressive breast cancer cells.
Loss of tumor-derived SMAD4 enhances primary tumor growth but not metastasis following BMP4 signalling.
LncRNA DLG5-AS1 facilitates breast cancer cell proliferation and invasion by promoting EZH2-mediated transcriptional silencing of SFRP1.
Breast Cancer Screening: Can We Justify Deescalation?
Abrogating PDK4 activates autophagy-dependent ferroptosis in breast cancer via ASK1/JNK pathway.
Clinicopathological Significance and Prognostic Role of High Mobility Group Box 1 (HMGB1), Toll-Like Receptor (TLR) 2 and TLR4 in Breast Cancer.
Neuroendocrine Breast Tumors: Could Multigene Assays Help in Guiding Treatment Decisions? Case Presentation.
CAR-based immunotherapy for breast cancer: peculiarities, ongoing investigations, and future strategies.
Role of cancer stem cell ecosystem on breast cancer metastasis and related mouse models.
High Throughput Bioprinting Using Decellularized Adipose Tissue-Based Hydrogels for 3D Breast Cancer Modeling.
Epithelial Expressed B7-H4 Drives Differential Immunotherapy Response in Murine and Human Breast Cancer.
Stratification and prognostic evaluation of breast cancer subtypes defined by obesity-associated genes.
Evolution of neoadjuvant therapy for breast cancer regimens over 12 years and pathologic response rates according to tumor subtypes and clinical stage: A single-center retrospective study.
Using genome and transcriptome data from African-ancestry female participants to identify putative breast cancer susceptibility genes.
GLP-1 receptor agonist as an effective treatment for breast cancer-related lymphedema: a case report.
Multicenter Study on Breast Cancer in the Geriatric Population: Insights for Effective Treatment Strategies.
A novel immune‑related lncRNA as a prognostic biomarker in HER2+ breast cancer.
Senescent CAFs mediate immunosuppression and drive breast cancer progression.
[Quantitative HER2 mRNA assay in breast cancer with HER2 immunohistochemistry 0].
Systematic Review of Survival Outcomes of Pregnancy-Associated Breast Cancer in Asian Countries.
Radiation Therapy for Breast Cancer in Africa.
Endothelial dysfunction in breast cancer survivors on aromatase inhibitors: changes over time.
Methylation of the chromatin modifier KMT2D by SMYD2 contributes to therapeutic response in hormone-dependent breast cancer.
Lipoic acid alters the microRNA signature in breast cancer cells.
Synergistic effects of miR-143 with miR-99a inhibited cell proliferation and induced apoptosis in breast cancer.
Correlation of IDH1 gene expression error in breast tumor biopsy in patients with invasive ductal carcinoma.
Metochalcone induces senescence-associated secretory phenotype via JAK2/STAT3 pathway in breast cancer.

Front Immunol. 2024 ;15 1381970

Targeting metabolism of breast cancer and its implications in T cell immunotherapy.

Jialuo Zou, Cunjun Mai, Zhiqin Lin, Jian Zhou, Guie Lai.

  Breast cancer is a prominent health issue amongst women around the world. Immunotherapies including tumor targeted antibodies, adoptive T cell therapy, vaccines, and immune checkpoint blockers have rejuvenated the clinical management of breast cancer, but the prognosis of patients remains dismal. Metabolic reprogramming and immune escape are two important mechanisms supporting the progression of breast cancer. The deprivation uptake of nutrients (such as glucose, amino acid, and lipid) by breast cancer cells has a significant impact on tumor growth and microenvironment remodeling. In recent years, in-depth researches on the mechanism of metabolic reprogramming and immune escape have been extensively conducted, and targeting metabolic reprogramming has been proposed as a new therapeutic strategy for breast cancer. This article reviews the abnormal metabolism of breast cancer cells and its impact on the anti-tumor activity of T cells, and further explores the possibility of targeting metabolism as a therapeutic strategy for breast cancer.

Keywords:  T cell immunotherapy; amino acid; breast cancer; glucose; immune escape; lipid; metabolic reprogramming

DOI:  https://doi.org/10.3389/fimmu.2024.1381970
Cancer Prev Res (Phila). 2024 May 03.

Diet modulates the gut microbiome, metabolism, and mammary gland inflammation to influence breast cancer risk.

Alana A Arnone, Adam S Wilson, David R Soto-Pantoja, Katherine L Cook.

Several studies have indicated a strong link between obesity and the risk of breast cancer. Obesity decreases gut microbial biodiversity and modulates Bacteroidetes-to-Firmicutes proportional abundance, suggesting that increased energy-harvesting capacity from indigestible dietary fibers and elevated lipopolysaccharide bioavailability may promote inflammation. To address the limited evidence linking diet-mediated changes in the gut microbiota to breast cancer risk, we aimed to determine how diet affects the microbiome and breast cancer risk. Female 3-week-old BALB/c mice were fed six different diets (control, high-sugar, lard, coconut oil, lard+flaxseed oil, and lard+safflower oil) for 10 weeks. Fecal 16s sequencing was performed for each group. Diet shifted fecal microbiome populations and modulated mammary gland macrophage infiltration. Fecal conditioned media shifted macrophage polarity and inflammation. In our DMBA-induced breast cancer model, diet differentially modulated tumor and mammary gland metabolism. We demonstrated how dietary patterns change metabolic outcomes, and gut microbiota, which may contribute to breast tumor risk. Furthermore, we showed the influence of diet on metabolism, inflammation, and macrophage polarity. This study suggests that dietary-microbiome interactions are key mediators of breast cancer risk.

DOI: https://doi.org/10.1158/1940-6207.CAPR-24-0055
Aust N Z J Obstet Gynaecol. 2024 Apr 30.

Why does hormonal contraception and menopausal hormonal treatment have such a small effect on breast cancer risk?

John A Eden.

  Oestrogen is considered by many to be a major cause of breast cancer, and yet hormonal contraception and menopausal hormonal therapy have a paradoxically small effect on breast cancer risk. Also, in the oestrogen-only arm of the Women's Health Initiative, subjects given oestrogen had a reduced risk of breast cancer compared to controls. Initiation of breast cancer likely begins early in life, in the long-lived ER-PR- breast stem cell. The main mitogen of ER+PR+ breast cancers is oestrogen derived from local breast fat and the tumour itself, rather than circulating oestrogens. Progesterone is relatively breast neutral, but progestins in the laboratory have been shown to expand malignant breast stem cell number.

Keywords:  breast cancer; causality; contraception; menopausal hormone therapy; risk factor

DOI:  https://doi.org/10.1111/ajo.13825
Sci Total Environ. 2024 Apr 26. pii: S0048-9697(24)02929-2. [Epub ahead of print] 172782

Triclocarban and triclosan promote breast cancer progression in vitro and in vivo via activating G protein-coupled estrogen receptor signaling pathways.

Ting-Ting He, Xin Li, Jie-Zhi Ma, Yuan Yang, Shiye Zhu, Jianhua Zeng, Lin Luo, Yu-Long Yin, Lin-Ying Cao.

  Triclocarban (TCC) and triclosan (TCS) have been detected ubiquitously in human body and evoked increasing concerns. This study aimed to reveal the induction risks of TCC and TCS on triple negative breast cancer through non-genomic GPER-mediated signaling pathways. Molecular simulation indicated that TCC exhibited higher GPER binding affinity than TCS theoretically. Calcium mobilization assay displayed that TCC/TCS activated GPER signaling pathway with the lowest observed effective concentrations (LOEC) of 10 nM/100 nM. TCC and TCS also upregulated MMP-2/9, EGFR, MAPK3 but downregulated MAPK8 via GPER-mediated signaling pathway. Proliferation assay showed that TCC/TCS induced 4 T1 breast cancer cells proliferation with the LOEC of 100 nM/1000 nM. Wound-healing and transwell assays showed that TCC/TCS promoted 4 T1 cells migration in a concentration-dependent manner with the LOEC of 10 nM. The effects of TCC on breast cancer cells proliferation and migration were stronger than TCS and both were regulated by GPER. TCC/TCS induced migratory effects were more significantly than proliferative effect. Mechanism study showed that TCC/TCS downregulated the expression of epithelial marker (E-cadherin) but upregulated mesenchymal markers (snail and N-cadherin), which was reversed by GPER inhibitor G15. These biomarkers results indicated that TCC/TCS-induced 4 T1 cells migration was a classic epithelial to mesenchymal transition mechanism regulated by GPER signaling pathway. Orthotopic tumor model verified that TCC promoted breast cancer in-situ tumor growth and distal tissue metastasis via GPER-mediated signaling pathway at human-exposure level of 10 mg/kg/d. TCC-induced tissue metastasis of breast cancer was more significantly than in-situ tumor growth. Overall, we demonstrated for the first time that TCC/TCS could activate the GPER signaling pathways to induce breast cancer progression.

Keywords:  Breast cancer; Estrogenic disruption; G protein-coupled estrogen receptor; Triclocarban; Triclosan

DOI:  https://doi.org/10.1016/j.scitotenv.2024.172782
Breast Cancer (Dove Med Press). 2024 ;16 233-243

Expression and Significance of LINC02418 in Breast Cancer.

Yong-Hong Zhou, Jian-Yuan Huang.

  Purpose: The complicated pathogenesis and poor prognosis of breast cancer have become a major difficulty in medical research. This study aims to explore new lncRNA as prognostic markers for breast cancer and explore their roles and molecular mechanisms to lay a foundation for the treatment of cancer patients.Patients and Methods: The expression of LINC02418 and miR-766-5p in breast cancer tissues and cells was first identified using polymerase chain reaction, and Pearson was used to examine the correlation between the two. The cancer cells activities under different transfection conditions were detected using the Transwell assay and CCK8 assay. The correlation between LINC02418 and patient prognosis was analyzed using multifactor Cox regression and Kaplan-Meier.
Results: It was shown that LINC02418 expression was upregulated in breast cancer tissues and cells. There are significant differences in lymph node metastasis and TNM stage between high and low LINC02418 expression groups. The higher the expression of LINC02418, the higher the mortality rate of breast cancer patients. miR-766-5p expression was downregulated and negatively correlated with LINC02418. There are binding sites between LINC02418 and miR-766-5p; Transfection with miR-766-5p inhibitor boosted LINC02418 luciferase activity, but transfection with miR-766-5p mimic decreased it. Knockdown of LINC02418 promoted miR-766-5p expression and inhibited cancer progression, which was alleviated to some extent by transfection with miR-766-5p inhibitors.
Conclusion: LINC02418 has the potential to serve as a poor prognostic marker for breast cancer and plays a pro-oncogenic role by targeting miR-766-5p.

Keywords:  LINC02418; breast cancer; cellular processes; miR-766-5p; prognosis

DOI:  https://doi.org/10.2147/BCTT.S454054
Curr Diabetes Rev. 2024 Apr 26.

Impaired Fibroblast Growth Factor 21 (FGF21) Associated with Visceral Adiposity Leads to Insulin Resistance: The Core Defect in Diabetes Mellitus.

Unnati Jain, Priyanka Srivastava, Ashwani Sharma, Subrata Sinha, Surabhi Johari.

  The Central nervous system (CNS) is the prime regulator of signaling pathways whose function includes regulation of food intake (consumption), energy expenditure, and other metabolic responses like glycolysis, gluconeogenesis, fatty acid oxidation, and thermogenesis that have been implicated in chronic inflammatory disorders. Type 2 diabetes mellitus (T2DM) and obesity are two metabolic disorders that are linked together and have become an epidemic worldwide, thus raising significant public health concerns. Fibroblast growth factor 21 (FGF21) is an endocrine hormone with pleiotropic metabolic effects that increase insulin sensitivity and energy expenditure by elevating thermogenesis in brown or beige adipocytes, thus reducing body weight and sugar intake. In contrast, during starvation conditions, FGF21 induces its expression in the liver to initiate glucose homeostasis. Insulin resistance is one of the main anomalies caused by impaired FGF21 signaling, which also causes abnormal regulation of other signaling pathways. Tumor necrosis factor alpha (TNF-α), the cytokine released by adipocytes and inflammatory cells in response to chronic inflammation, is regarded major factor that reduces the expression of FGF21 and modulates underlying insulin resistance that causes imbalanced glucose homeostasis. This review aims to shed light on the mechanisms underlying the development of insulin resistance in obese individuals as well as the fundamental flaw in type 2 diabetes, which is malfunctioning obese adipose tissue.

Keywords:  Fibroblast Growth Factor 21; Glucose Homeostasis; Insulin Resistance; Obesity; Thermogenesis; Tumor Necrosis Factor (TNF); Type ll Diabetes Mellitus

DOI:  https://doi.org/10.2174/0115733998265915231116043813
Iran J Public Health. 2024 Jan;53(1): 208-218

MiR-103a-3p Promotes Tumorigenesis of Breast Cancer by Targeting ETNK1.

Lei Li, Aifeng Qiu, Yuhua Shi.

  Background: We aimed to elucidate the molecular mechanism of miR-103a-3p regulating breast cancer progression.Methods: Firstly, clinical tissues was obtained from 2019-2023 at Yancheng Third People's Hospital, Yancheng, China. miR-103a-3p or ETNK1 expression in clinical tissues or breast cancer cell lines was analyzed with qRTPCR. MDA-MB-231 cells were performed with miR-103a-3p inhibitor or mimic, and OE-ETNK1. The proliferation and apoptosis ability were detected by CCK-8 and TUNEL assay. The xenograft models were established by inoculating transfected MDA-MB-231 cells to BALB/c mice.
Results: miR-103a-3p showed an overexpression and was related to poor prognosis in breast cancer. miR-103a-3p-deprived MDA-MB-231 cells displayed weaker levels of cell proliferation and higher rates of apoptosis. In contrast, ETNK1 was downregulated in breast cancer and proved to be a downstream target of miR-103a-3p. Xenograft models subjected to either miR-103a-3p antagomir treatment or ETNK1-knockdown resulted in tumor growth suppression.
Conclusion: miR-103a-3p might promote breast cancer progression by inhibiting ETNK1.

Keywords:  Apoptosis; Breast cancer; MiR-103a-3p; Proliferation

DOI:  https://doi.org/10.18502/ijph.v53i1.14697
Colloids Surf B Biointerfaces. 2024 Apr 25. pii: S0927-7765(24)00189-9. [Epub ahead of print]238 113930

MCT4 knockdown by tumor microenvironment-responsive nanoparticles remodels the cytokine profile and eradicates aggressive breast cancer cells.

Ahmed A H Abdellatif, Abdellatif Bouazzaoui, Hesham M Tawfeek, Mahmoud A Younis.

  Breast cancer is a wide-spread threat to the women's health. The drawbacks of conventional treatments necessitate the development of alternative strategies, where gene therapy has regained hope in achieving an efficient eradication of aggressive tumors. Monocarboxylate transporter 4 (MCT4) plays pivotal roles in the growth and survival of various tumors, which offers a promising target for treatment. In the present study, pH-responsive lipid nanoparticles (LNPs) based on the ionizable lipid,1,2-dioleoyl-3-dimethylammonium propane (DODAP), were designed for the delivery of siRNA targeting MCT4 gene to the breast cancer cells. Following multiple steps of characterization and optimization, the anticancer activities of the LNPs were assessed against an aggressive breast cancer cell line, 4T1, in comparison with a normal cell line, LX-2. The selection of the helper phospholipid to be incorporated into the LNPs had a dramatic impact on their gene delivery performance. The optimized LNPs enabled a powerful MCT4 silencing by ∼90 % at low siRNA concentrations, with a subsequent ∼80 % cytotoxicity to 4T1 cells. Meanwhile, the LNPs demonstrated a 5-fold higher affinity to the breast cancer cells versus the normal cells, in which they had a minimum effect. Moreover, the MCT4 knockdown by the treatment remodeled the cytokine profile in 4T1 cells, as evidenced by 90 % and ∼64 % reduction in the levels of TNF-α and IL-6; respectively. The findings of this study are promising for potential clinical applications. Furthermore, the simple and scalable delivery vector developed herein can serve as a breast cancer-targeting platform for the delivery of other RNA therapeutics.

Keywords:  Clinical translation; Gene therapy; Lipid nanoparticles; MCT4; Reast cancer

DOI:  https://doi.org/10.1016/j.colsurfb.2024.113930
Cell Commun Signal. 2024 Apr 30. 22(1): 248

Loss of tumor-derived SMAD4 enhances primary tumor growth but not metastasis following BMP4 signalling.

Lap Hing Chi, Andrew D Redfern, Suraya Roslan, Ian P Street, Allan D Burrows, Robin L Anderson.

  BACKGROUND: Bone morphogenetic protein 4 (BMP4) is a potent inhibitor of breast cancer metastasis. However, a tumor-promoting effect of BMP4 is reported in other tumor types, especially when SMAD4 is inactive.METHODS: To assess the requirement for SMAD4 in BMP4-mediated suppression of metastasis, we knocked down SMAD4 in two different breast tumors and enforced SMAD4 expression in a third line with endogenous SMAD4 deletion. In addition, we assessed the requirement for SMAD4 in tumor cell-specific BMP signalling by expression of a constitutively active BMP receptor. Delineation of genes regulated by BMP4 in the presence or absence of SMAD4 was assessed by RNA sequencing and a BMP4-induced gene, MYO1F was assessed for its role in metastasis. Genes regulated by BMP4 and/or SMAD4 were assessed in a publicly available database of gene expression profiles of breast cancer patients.
RESULTS: In the absence of SMAD4, BMP4 promotes primary tumor growth that is accompanied by increased expression of genes associated with DNA replication, cell cycle, and MYC signalling pathways. Despite increased primary tumor growth, BMP4 suppresses metastasis in the absence of tumor cell expression of SMAD4. Consistent with the anti-metastatic activity of BMP4, enforced signalling through the constitutively active receptor in SMAD4 positive tumors that lacked BMP4 expression still suppressed metastasis, but in the absence of SMAD4, the suppression of metastasis was largely prevented. Thus BMP4 is required for suppression of metastasis regardless of tumor SMAD4 status. The BMP4 upregulated gene, MYO1F, was shown to be a potent suppressor of breast cancer metastasis. Gene signature upregulated by BMP4 in the absence of SMAD4 was associated with poor prognosis in breast cancer patients, whereas gene signature upregulated by BMP4 in the presence of SMAD4 was associated with improved prognosis.
CONCLUSIONS: BMP4 expression is required for suppression of metastasis regardless of the SMAD4 status of the tumor cells. Since BMP4 is a secreted protein, we conclude that it can act both in an autocrine manner in SMAD4-expressing tumor cells and in a paracrine manner on stromal cells to suppress metastasis. Deletion of SMAD4 from tumor cells does not prevent BMP4 from suppressing metastasis via a paracrine mechanism.

Keywords:  BMP4; Breast cancer; MYO1F; Metastasis; Patient outcomes; SMAD4

DOI:  https://doi.org/10.1186/s12964-024-01559-0
Arch Biochem Biophys. 2024 Apr 26. pii: S0003-9861(24)00137-1. [Epub ahead of print]756 110018

LncRNA DLG5-AS1 facilitates breast cancer cell proliferation and invasion by promoting EZH2-mediated transcriptional silencing of SFRP1.

Yun Cai, Yi Liu, Ye Sun, Yu Ren.

  Rapid proliferation and metastasis of breast cancer contributed to poor clinical prognosis. Accumulating evidence revealed that the dysregulation of long noncoding RNAs (lncRNAs) was associated with breast cancer progression. However, the role of lncRNA DLG5-AS1 in breast cancer has not been established. Here, we investigated the mechanisms of DLG5-AS1 in the development of breast cancer. We found that the expression of DLG5-AS1 was significantly upregulated in breast cancer tissues and cell lines. DLG5-AS1 interference markedly restrained AU565 cell proliferation, invasion, the expression of apoptosis related (caspase3 and caspase8) and Wnt/β-catenin pathway related proteins (wnt5a, β-Catenin and c-Myc), as well as promoted cell apoptosis, whereas DLG5-AS1 overexpression showed an opposite effects. In addition, DLG5-AS1 could directly bind with miR-519 b-3p. We also found that enhancer of zeste homolog 2 (EZH2) is a direct target of miR-519 b-3p, and DLG5-AS1 upregulated EZH2 expression by inhibiting the expression of miR-519 b-3p. EZH2 restrained secreted frizzled related protein 1 (SFRP1) expression through inducing H3 histone methylation in its promoter. MiR-519 b-3p overexpression or SFRP1 knockdown memorably reversed the effects of DLG5-AS1 overexpression on cell functions and Wnt/β-Catenin pathway related protein expression. Finally, in vivo experiments demonstrated that silencing of DLG5-AS1 inhibited xenograft tumor development in mice. Taken together, these findings demonstrated that DLG5-AS1 facilitated cell proliferation and invasion by promoting EZH2-mediated transcriptional silencing of SFRP1 in breast cancer.

Keywords:  Breast cancer; EZH2; SFRP1; The wnt/β-catenin pathway; lncRNA DLG5-AS1; miR-519b-3p

DOI:  https://doi.org/10.1016/j.abb.2024.110018
Cancer Epidemiol Biomarkers Prev. 2024 May 01. 33(5): 638-640

Breast Cancer Screening: Can We Justify Deescalation?

Ismail Jatoi.

Novel breast cancer screening methods that detect greater numbers of occult (nonpalpable) tumors have been rapidly incorporated into clinical practice, with the aim of reducing mortality. Yet, tumor detection has never been validated as a proper surrogate outcome measure for breast cancer mortality. Moreover, the detection of greater numbers of occult cancers increases the risk of overdiagnosis, which refers to detection of tumors that pose no threat to life and would never have been detected in the absence of screening. With recent advances in breast cancer therapy, many cancers that were previously curable only if detected as occult tumors with mammography screening are perhaps now curable even when detected as small palpable tumors, thereby giving us an opportunity to deescalate screening and mitigate the risk of overdiagnosis. Thus, a randomized trial comparing screening mammography versus screening clinical breast examination (CBE), with breast cancer mortality as the endpoint, is now warranted. In such a trial, hand-held ultrasound might aid in the interpretation of screening CBE findings. In conclusion, recent improvements in breast cancer therapy provide the justification to assess the deescalation of breast cancer screening. See related article by Farber et al., p. 671.

DOI: https://doi.org/10.1158/1055-9965.EPI-23-1597
J Cancer Res Clin Oncol. 2024 Apr 27. 150(4): 218

Abrogating PDK4 activates autophagy-dependent ferroptosis in breast cancer via ASK1/JNK pathway.

Wenbiao Shi, Jian Wang, Jianbin Chen, Xiaoyan Jin, Yuanfan Wang, Linjun Yang.

  BACKGROUND: Targeting ferroptosis mediated by autophagy presents a novel therapeutic approach to breast cancer, a mortal neoplasm on the global scale. Pyruvate dehydrogenase kinase isozyme 4 (PDK4) has been denoted as a determinant of breast cancer metabolism. The target of this study was to untangle the functional mechanism of PDK4 in ferroptosis dependent on autophagy in breast cancer.METHODS: RT-qPCR and western blotting examined PDK4 mRNA and protein levels in breast cancer cells. Immunofluorescence staining appraised light chain 3 (LC3) expression. Fe (2 +) assay estimated total iron level. Relevant assay kits and C11-BODIPY (591/581) staining evaluated lipid peroxidation level. DCFH-DA staining assayed intracellular reactive oxygen species (ROS) content. Western blotting analyzed the protein levels of autophagy, ferroptosis and apoptosis-signal-regulating kinase 1 (ASK1)/c-Jun N-terminal kinase (JNK) pathway-associated proteins.
RESULTS: PDK4 was highly expressed in breast cancer cells. Knockdown of PDK4 induced the autophagy of breast cancer cells and 3-methyladenine (3-MA), an autophagy inhibitor, countervailed the promoting role of PDK4 interference in ferroptosis in breast cancer cells. Furthermore, PDK4 knockdown activated ASK1/JNK pathway and ASK1 inhibitor (GS-4997) partially abrogated the impacts of PDK4 absence on the autophagy and ferroptosis in breast cancer cells.
CONCLUSION: To sum up, deficiency of PDK4 activated ASK1/JNK pathway to stimulate autophagy-dependent ferroptosis in breast cancer.

Keywords:  ASK1/JNK pathway; Autophagy; Breast cancer; Ferroptosis; PDK4

DOI:  https://doi.org/10.1007/s00432-024-05748-9
Acta Histochem Cytochem. 2024 Apr 25. 57(2): 75-83

Clinicopathological Significance and Prognostic Role of High Mobility Group Box 1 (HMGB1), Toll-Like Receptor (TLR) 2 and TLR4 in Breast Cancer.

Reina Taguchi, Mio Yamaguchi-Tanaka, Kiyoshi Takagi, Ai Sato, Yasuhiro Miki, Minoru Miyashita, Takashi Suzuki.

  High-mobility group box 1 (HMGB1) functions as damage-associated molecular pattern (DAMPs), released into extracellular space during cellular stress. Extracellular HMGB1 act as signal molecules through Toll-like receptor (TLR) 2 or TLR4, exerting diverse functions in both normal cells and malignant cells including breast cancer. However, their comprehensive examination in breast cancer tissues is lacking. Thus, we immunolocalized them in 112 breast cancer tissues, correlating their immunoreactivity with clinicopathological parameters and clinical outcomes to clarify their significance in breast cancer. We demonstrated that nuclear HMGB1 immunoreactivity was correlated with tumor progression and longer disease-free survival. In contrast, TLR2 immunoreactivity was correlated with increased cell proliferation and shorter disease-free survival, dependent on cytoplasmic HMGB1 immunoreactivity. Additionally, TLR4 immunoreactivity correlated with chemoresistance, regardless of cytoplasmic HMGB1 immunoreactivity. It was therefore considered that TLR2 collaboratively contributed to breast cancer progression with HMGB1-DAMPs to become a worse prognostic factor. Meanwhile, TLR4 served as a worse prognostic factor associated with chemoresistance, irrespective of HMGB1.

Keywords:  HMGB1; Toll-like receptor; breast cancer; immunohistochemistry; prognostic factor

DOI:  https://doi.org/10.1267/ahc.24-00006
In Vivo. 2024 May-Jun;38(3):38(3): 1443-1447

Neuroendocrine Breast Tumors: Could Multigene Assays Help in Guiding Treatment Decisions? Case Presentation.

Christos Markopoulos, Nikolaos Tsoulos, Konstantinos Agiannitopoulos, Evangelia Karagianni.

  BACKGROUND/AIM: Breast cancer remains the most prevalent type of cancer among women worldwide, and it remains the primary cause of cancer-related deaths in this demographic. Neuroendocrine breast cancer (NBC), an uncommon subtype comprising less than 1% of cases, typically occurs in older women and displays as a slow-growing, low-grade condition. NBC exhibits distinct histological patterns and immunohistochemical markers. Given the limited data on NBC, assays are required that will provide information on molecular profiling and assist in clinical decision making. The aim of the study was to investigate whether a modern Multigene Assay (MGA) could assist on treatment planning of NBC patients.CASE REPORT: A cohort of four patients was analyzed using a MGA. The presented cases featured young, pre-menopausal women with clear NBC, lacking family history. All were lymph node-negative, with robust expression of neuroendocrine markers. Despite high hormone receptor expression, all tumors were poorly differentiated with elevated Ki67 levels. Oncotype DX analysis indicated a need for chemotherapy in three cases and not in one. This underscores the heterogeneity within NBC, emphasizing the importance of personalized treatment decisions.
CONCLUSION: While NBC is rare and lacks extensive studies, the use of multigene assays like Oncotype DX may play a pivotal role in treatment planning, especially in cases with varying histological parameters.

Keywords:  Breast cancer; OncotypeDX; neuroendocrine breast tumor; recurrence score

DOI:  https://doi.org/10.21873/invivo.13587
Front Immunol. 2024 ;15 1385571

CAR-based immunotherapy for breast cancer: peculiarities, ongoing investigations, and future strategies.

Zhipu Niu, Jingyuan Wu, Qiancheng Zhao, Jinyu Zhang, Pengyu Zhang, Yiming Yang.

  Surgery, chemotherapy, and endocrine therapy have improved the overall survival and postoperative recurrence rates of Luminal A, Luminal B, and HER2-positive breast cancers but treatment modalities for triple-negative breast cancer (TNBC) with poor prognosis remain limited. The effective application of the rapidly developing chimeric antigen receptor (CAR)-T cell therapy in hematological tumors provides new ideas for the treatment of breast cancer. Choosing suitable and specific targets is crucial for applying CAR-T therapy for breast cancer treatment. In this paper, we summarize CAR-T therapy's effective targets and potential targets in different subtypes based on the existing research progress, especially for TNBC. CAR-based immunotherapy has resulted in advancements in the treatment of breast cancer. CAR-macrophages, CAR-NK cells, and CAR-mesenchymal stem cells (MSCs) may be more effective and safer for treating solid tumors, such as breast cancer. However, the tumor microenvironment (TME) of breast tumors and the side effects of CAR-T therapy pose challenges to CAR-based immunotherapy. CAR-T cells and CAR-NK cells-derived exosomes are advantageous in tumor therapy. Exosomes carrying CAR for breast cancer immunotherapy are of immense research value and may provide a treatment modality with good treatment effects. In this review, we provide an overview of the development and challenges of CAR-based immunotherapy in treating different subtypes of breast cancer and discuss the progress of CAR-expressing exosomes for breast cancer treatment. We elaborate on the development of CAR-T cells in TNBC therapy and the prospects of using CAR-macrophages, CAR-NK cells, and CAR-MSCs for treating breast cancer.

Keywords:  CAR-M; CAR-NK; CAR-T; TME; TNBC; breast cancer; exosome

DOI:  https://doi.org/10.3389/fimmu.2024.1385571
Zool Res. 2024 May 18. pii: 2095-8137(2024)03-0506-12. [Epub ahead of print]45(3): 506-517

Role of cancer stem cell ecosystem on breast cancer metastasis and related mouse models.

Xilei Peng, Haonan Dong, Lixing Zhang, Suling Liu.

  Breast cancer metastasis is responsible for most breast cancer-related deaths and is influenced by many factors within the tumor ecosystem, including tumor cells and microenvironment. Breast cancer stem cells (BCSCs) constitute a small population of cancer cells with unique characteristics, including their capacity for self-renewal and differentiation. Studies have shown that BCSCs not only drive tumorigenesis but also play a crucial role in promoting metastasis in breast cancer. The tumor microenvironment (TME), composed of stromal cells, immune cells, blood vessel cells, fibroblasts, and microbes in proximity to cancer cells, is increasingly recognized for its crosstalk with BCSCs and role in BCSC survival, growth, and dissemination, thereby influencing metastatic ability. Hence, a thorough understanding of BCSCs and the TME is critical for unraveling the mechanisms underlying breast cancer metastasis. In this review, we summarize current knowledge on the roles of BCSCs and the TME in breast cancer metastasis, as well as the underlying regulatory mechanisms. Furthermore, we provide an overview of relevant mouse models used to study breast cancer metastasis, as well as treatment strategies and clinical trials addressing BCSC-TME interactions during metastasis. Overall, this study provides valuable insights for the development of effective therapeutic strategies to reduce breast cancer metastasis.

Keywords:  Breast cancer; Cancer stem cell; Ecosystem; Metastasis; Mouse model; Tumor microenvironment

DOI:  https://doi.org/10.24272/j.issn.2095-8137.2023.411
Macromol Biosci. 2024 Apr 29. e2400035

High Throughput Bioprinting Using Decellularized Adipose Tissue-Based Hydrogels for 3D Breast Cancer Modeling.

Priyanshu Shukla, Ashis Kumar Bera, Sriya Yeleswarapu, Falguni Pati.

  3D bioprinting allows rapid automated fabrication and can be applied for high throughput generation of biomimetic constructs for in vitro drug screening. Decellularized extracellular matrix (dECM) hydrogel is a popular biomaterial choice for tissue engineering and studying carcinogenesis as a tumor microenvironmental mimetic. This study proposes a method for high throughput bioprinting with decellularized adipose tissue (DAT) based hydrogels for 3D breast cancer modeling. A comparative analysis of decellularization protocol using detergent-based and detergent-free decellularization methods for caprine-origin adipose tissue is performed, and the efficacy of dECM hydrogel for 3D cancer modeling is assessed. Histological, biochemical, morphological, and biological characterization and analysis showcase the cytocompatibility of DAT hydrogel. The rheological property of DAT hydrogel and printing process optimization is assessed to select a bioprinting window to attain 3D breast cancer models. The bioprinted tissues are characterized for cellular viability and tumor cell-matrix interactions. Additionally, an approach for breast cancer modeling is shown by performing rapid high throughput bioprinting in a 96-well plate format, and in vitro drug screening using 5-fluorouracil is performed on 3D bioprinted microtumors. The results of this study suggest that high throughput bioprinting of cancer models can potentially have downstream clinical applications like multi-drug screening platforms and personalized disease models.

Keywords:  3D bioprinting; adipose tissue; breast cancer; decellularized extracellular matrix hydrogel; high throughput

DOI:  https://doi.org/10.1002/mabi.202400035
Cancer Res Commun. 2024 Apr 24. 4(4): 1120-1134

Epithelial Expressed B7-H4 Drives Differential Immunotherapy Response in Murine and Human Breast Cancer.

Elizabeth C Wescott, Xiaopeng Sun, Paula Gonzalez-Ericsson, Ann Hanna, Brandie C Taylor, Violeta Sanchez, Juliana Bronzini, Susan R Opalenik, Melinda E Sanders, Julia Wulfkuhle, Rosa I Gallagher, Henry Gomez, Claudine Isaacs, Vijaya Bharti, John T Wilson, Tarah J Ballinger, Cesar A Santa-Maria, Payal D Shah, Elizabeth C Dees, Brian D Lehmann, Vandana G Abramson, Gillian L Hirst, Lamorna Brown Swigart, Laura J van ˈt Veer, Laura J Esserman, Emanuel F Petricoin, Jennifer A Pietenpol, Justin M Balko.

Combinations of immune checkpoint inhibitors (ICI, including anti-PD-1/PD-L1) and chemotherapy have been FDA approved for metastatic and early-stage triple-negative breast cancer (TNBC), but most patients do not benefit. B7-H4 is a B7 family ligand with proposed immunosuppressive functions being explored as a cancer immunotherapy target and may be associated with anti-PD-L1 resistance. However, little is known about its regulation and effect on immune cell function in breast cancers. We assessed murine and human breast cancer cells to identify regulation mechanisms of B7-H4 in vitro. We used an immunocompetent anti-PD-L1-sensitive orthotopic mammary cancer model and induced ectopic expression of B7-H4. We assessed therapy response and transcriptional changes at baseline and under treatment with anti-PD-L1. We observed B7-H4 was highly associated with epithelial cell status and transcription factors and found to be regulated by PI3K activity. EMT6 tumors with cell-surface B7-H4 expression were more resistant to immunotherapy. In addition, tumor-infiltrating immune cells had reduced immune activation signaling based on transcriptomic analysis. Paradoxically, in human breast cancer, B7-H4 expression was associated with survival benefit for patients with metastatic TNBC treated with carboplatin plus anti-PD-L1 and was associated with no change in response or survival for patients with early breast cancer receiving chemotherapy plus anti-PD-1. While B7-H4 induces tumor resistance to anti-PD-L1 in murine models, there are alternative mechanisms of signaling and function in human cancers. In addition, the strong correlation of B7-H4 to epithelial cell markers suggests a potential regulatory mechanism of B7-H4 independent of PD-L1.SIGNIFICANCE: This translational study confirms the association of B7-H4 expression with a cold immune microenvironment in breast cancer and offers preclinical studies demonstrating a potential role for B7-H4 in suppressing response to checkpoint therapy. However, analysis of two clinical trials with checkpoint inhibitors in the early and metastatic settings argue against B7-H4 as being a mechanism of clinical resistance to checkpoints, with clear implications for its candidacy as a therapeutic target.

DOI: https://doi.org/10.1158/2767-9764.CRC-23-0468
Discov Oncol. 2024 Apr 27. 15(1): 133

Stratification and prognostic evaluation of breast cancer subtypes defined by obesity-associated genes.

Dongjuan Chen, Zilu Xie, Jun Yang, Ting Zhang, Qiliang Xiong, Chen Yi, Shaofeng Jiang.

  OBJECTIVE: Breast cancer was the most common type of cancer among women worldwide, significantly impacting their quality of life and survival rates. And obesity has been widely accepted as an important risk factor for breast cancer. However, the specific mechanisms by which obesity affects breast cancer were still unclear. Therefore, studying the impact mechanisms of obesity as a risk factor for breast cancer was of utmost importance.METHODS: This study was based on TCGA breast cancer RNA transcriptomic data and the GeneCard obesity gene set. Through single and multiple factor Cox analysis and LASSO coefficient screening, seven hub genes were identified. The independent mechanisms of these seven hub genes were evaluated from various aspects, including survival data, genetic mutation data, single-cell sequencing data, and immune cell data. Additionally, the risk prognosis model and the neural network diagnostic model were established to further investigate these seven hub genes. In order to achieve precision treatment for breast cancer (BRCA), based on the RNA transcriptomic data of the seven genes, 1226 BRCA patients were divided into two subtypes: BRCA subtype 1 and BRCA subtype 2. By studying and comparing the immune microenvironment, investigating the mechanisms of differential gene expression, and exploring the mechanisms of subnetworks, we aim to explore the clinical differences in the presentation of BRCA subtypes and achieve precision treatment for BRCA. Finally, qRT-PCR experiments were conducted to validate the conclusions of the bioinformatics analysis.
RESULTS: The 7 hub genes showed good diagnostic independence and can serve as excellent biomarkers for molecular diagnosis. However, they do not perform well as independent prognostic molecular markers for BRCA patients. When predicting the survival of BRCA patients, their AUC values at 1 year, 3 years, and 5 years are mostly below 0.5. Nevertheless, through the establishment of the risk prognosis model considering the combined effect of the seven hub genes, it was found that the survival prediction of BRCA patients can be significantly improved. The risk prognosis model, compared to the independent use of the seven hub genes as prognostic markers, achieved higher timeROC AUC values at 1 year, 3 years, and 5 years, with values of 0.651, 0.669, and 0.641 respectively. Additionally, the neural network diagnostic model constructed from the 7 genes performs well in diagnosing BRCA, with an AUC value of 0.94, accurately identifying BRCA patients. The two subtypes identified by the seven hub genes exhibited significant differences in survival period, with subtype 1 having a poor prognosis. The differential mechanisms between the two subtypes mainly originate from regulatory differences in the immune microenvironment. Finally, the results of this study's bioinformatics analysis were validated through qRT-PCR experiments.
CONCLUSION: 7 hub genes serve as excellent independent biomarkers for molecular diagnosis, and the neural network diagnostic model can accurately distinguish BRCA patients. In addition, based on the expression levels of these seven genes in BRCA patients, two subtypes can be reliably identified: BRCA subtype 1 and BRCA subtype 2, and these two subtypes showed significant differences in BRCA patient survival prognosis, proportion of immune cells, and expression levels of immune cells. Among them, patients with subtype 1 of BRCA had a poor prognosis.

Keywords:  Diagnosis; Inflammation; Obesity; Subtype identification

DOI:  https://doi.org/10.1007/s12672-024-00988-0
J Cancer Res Ther. 2024 Apr 01. 20(2): 608-614

Evolution of neoadjuvant therapy for breast cancer regimens over 12 years and pathologic response rates according to tumor subtypes and clinical stage: A single-center retrospective study.

Zhedong Li, Yongsheng Wang.

BACKGROUND AND PURPOSE: Given the evolution of neoadjuvant therapy (NAT) for breast cancer, this study aimed to analyze trends in NAT regimens over time and patients' pathological responses, tumor stages, and subtypes.MATERIALS AND METHODS: Data were analyzed for 548 patients with cT1-4N0-3M0 breast cancer who received NAT at Shandong Cancer Hospital between 2011 and 2022. The 12-year study period was divided into six 2-year periods termed P1 to P6.
RESULTS: From P1 to P6, the proportion of stage II patients treated with NAT increased from 6.4% to 33.8% compared with same-stage operable breast cancer (r = 0.228, P < 0.001), while the proportion of the full-course group increased from 50.0% to 99.0% (r = 0.354, P < 0.001). The pathologic complete remission (pCR) rate in the full-course group increased from 30.8% to 54.6% (r = 0.248, P < 0.001). In the full-course human epidermal growth factor receptor-2 positive (HER2+) group, the proportion of chemotherapy combined with inhibition therapy increased from 33.3% to 100% (r = 0.530, P < 0.001). Furthermore, dual inhibition therapy increased from 0 to 98.9%. The proportion of the nonanthracycline group (dual inhibition) increased from 56.0% at P5 to 76.6% at P6 (r = 0.190, P = 0.042). In the full-course Triple-Negative Breast Cancer (TNBC) group, the proportion of platinum therapy increased from 0 to 41.9% (r = 0.324, P < 0.001) and immune drugs increased from 0 to 53.2% (r = 0.500, P < 0.001).
CONCLUSION: Overall, the results indicate an increasing proportion of patients receiving NAT therapy over time. Furthermore, there were increases in HER2 + patients receiving inhibition therapy (especially dual inhibition) and TNBC patients receiving platinum and immune therapy as part of NAT. Notably, these changes were associated with improved outcomes.

DOI: https://doi.org/10.4103/jcrt.jcrt_1693_23
Nat Commun. 2024 May 02. 15(1): 3718

Using genome and transcriptome data from African-ancestry female participants to identify putative breast cancer susceptibility genes.

Jie Ping, Guochong Jia, Qiuyin Cai, Xingyi Guo, Ran Tao, Christine Ambrosone, Dezheng Huo, Stefan Ambs, Mollie E Barnard, Yu Chen, Montserrat Garcia-Closas, Jian Gu, Jennifer J Hu, Esther M John, Christopher I Li, Katherine Nathanson, Barbara Nemesure, Olufunmilayo I Olopade, Tuya Pal, Michael F Press, Maureen Sanderson, Dale P Sandler, Toshio Yoshimatsu, Prisca O Adejumo, Thomas Ahearn, Abenaa M Brewster, Anselm J M Hennis, Timothy Makumbi, Paul Ndom, Katie M O'Brien, Andrew F Olshan, Mojisola M Oluwasanu, Sonya Reid, Song Yao, Ebonee N Butler, Maosheng Huang, Atara Ntekim, Bingshan Li, Melissa A Troester, Julie R Palmer, Christopher A Haiman, Jirong Long, Wei Zheng.

African-ancestry (AA) participants are underrepresented in genetics research. Here, we conducted a transcriptome-wide association study (TWAS) in AA female participants to identify putative breast cancer susceptibility genes. We built genetic models to predict levels of gene expression, exon junction, and 3' UTR alternative polyadenylation using genomic and transcriptomic data generated in normal breast tissues from 150 AA participants and then used these models to perform association analyses using genomic data from 18,034 cases and 22,104 controls. At Bonferroni-corrected P < 0.05, we identified six genes associated with breast cancer risk, including four genes not previously reported (CTD-3080P12.3, EN1, LINC01956 and NUP210L). Most of these genes showed a stronger association with risk of estrogen-receptor (ER) negative or triple-negative than ER-positive breast cancer. We also replicated the associations with 29 genes reported in previous TWAS at P < 0.05 (one-sided), providing further support for an association of these genes with breast cancer risk. Our study sheds new light on the genetic basis of breast cancer and highlights the value of conducting research in AA populations.

DOI: https://doi.org/10.1038/s41467-024-47650-5
Front Oncol. 2024 ;14 1392375

GLP-1 receptor agonist as an effective treatment for breast cancer-related lymphedema: a case report.

Fionnuala Crowley, Stav Brown, Emily J Gallagher, Joseph H Dayan.

  Introduction: Lymphedema is a major public health issue for many women undergoing breast cancer treatment. Although weight loss has been reported to be beneficial in the treatment of lymphedema, no studies to date have examined the use of GLP-1RAs for the treatment of secondary lymphedema. This case report describes a patient who experienced significant resolution of her breast cancer-related lymphedema after initiation of a GLP-1RA for weight loss.Main symptoms and/or important clinical findings: Nine months postoperatively the patient developed arm swelling and disability. While on adjuvant chemo and hormonal therapy, her weight increased dramatically and peaked 4 years later. Corresponding to her weight gain was significant worsening of her symptoms.
The main diagnoses therapeutic interventions and outcomes: Due to adjuvant cancer-related weight gain and inability to lose weight with diet and exercise, she was referred for evaluation and diagnosed with lymphedema. The patient started treatment with a Glucagon-like peptide 1 receptor agonist and lost 24% of her body weight over the next 13 months. The improvement in her lymphedema mirrored her weight loss. Her limb volume difference dropped from 10.3% down to 3.4% and she no longer required a compression garment. Her imaging demonstrated return of lymphatic pumping and she experienced a significant improvement in quality of life, assessed by a validated lymphedema-specific patient reported outcome (PROM). She remains on hormonal therapy, no longer needs compression and is back to regular exercise without impairment.
Conclusions: GLP-1 RAs provide a potential medical option for many patients struggling with weight gain and lymphedema. We have observed by all objective measures a significant reduction in lymphedema and the elimination of compression in the case presented as a direct result of GLP-1 RA. This may also reduce a patient's BMI to the point where they become a good candidate for lymphovenous bypass or vascularized lymph node transplant when indicated.

Keywords:  GLP-1; GLP-1RA; breast cancer; cancer-related lymphedema; case report; glucagon-like peptide 1 receptor agonists; lymphedema

DOI:  https://doi.org/10.3389/fonc.2024.1392375
Cureus. 2024 Mar;16(3): e57253

Multicenter Study on Breast Cancer in the Geriatric Population: Insights for Effective Treatment Strategies.

Sule Karabulut Gul, Huseyin Tepetam, Berrin Benli Yavuz, Ozge Kandemir Gursel, Ayşe Altinok, Pelin Altinok, Ahmet Fatih Oruc, Duygu Akincioglu, Raghad Al Shomali, Omar Alomari, Mehmet Alper Kaya.

  OBJECTIVE: Breast cancer is common among women aged 65 and over. There is a significant lack of evidence regarding the treatment of breast cancer in patients in this age group due to the rare inclusion of these patients in clinical studies. However, it is known that survival in elderly patients with breast cancer is significantly reduced in those not receiving standard therapy. Several factors, including patients' comorbidities, performance status, life expectancy, and tumor pathological and molecular characteristics, can affect the outcomes of treatment. In this study, we aimed to update the knowledge in this field by assessing these factors among the geriatric population in our multicenter dataset.METHODS: This retrospective study analyzed data from 335 breast cancer patients aged 65 and over who received adjuvant radiotherapy at five oncology centers (Kartal Dr. Lutfi Kirdar Training and Research Hospital, Istanbul, Meram Medical Faculty - Necmettin Erbakan University, Konya, Prof. Dr. Cemil Tascioglu City Hospital, Istanbul, Umraniye Training and Research Hospital, Istanbul, and Istanbul Oncology Hospital, Istanbul) between May 2010 and September 2022. Demographic, clinical, and pathological data were collected, including age, gender, clinical symptoms, tumor characteristics, treatment approaches, and outcomes. Statistical analyses, including descriptive statistics, Kaplan-Meier analysis, log-rank test, and Cox regression analysis, were performed using IBM SPSS Statistics for Windows, Version 22 (Released 2013; IBM Corp., Armonk, New York, United States), with a significance level of p < 0.05.
RESULTS: The tumor characteristics and survival time of 335 breast cancer patients were examined. In the results, performance status, T stage, and perineural invasion were found to be factors affecting the survival of elderly breast cancer patients. In multivariate analysis, it was seen that performance status played an important role as an independent prognostic factor.
CONCLUSION: The treatment of breast cancer in the geriatric age group necessitates a personalized approach, taking into account the patient's overall health status, life expectancy, and comorbidities.

Keywords:  breast cancer; elderly patients; multicenter analysis; multicenter study; treatment approaches

DOI:  https://doi.org/10.7759/cureus.57253
Oncol Lett. 2024 Jun;27(6): 269

A novel immune‑related lncRNA as a prognostic biomarker in HER2+ breast cancer.

Xinwei Li, Yue Meng, Bing Gu.

  Human epidermal growth factor receptor 2 (HER2)+ breast cancer is characterized by high malignancy and poor prognosis. Long non-coding (lnc)RNAs are crucial in breast cancer progression and prognosis, especially in tumor-associated immune processes. The present study aimed to elucidate novel lncRNAs related to immune function that could serve as biomarkers for both diagnosis and prognosis of this cancer subtype. Using data from The Cancer Genome Atlas and The Immunology Database and Analysis Portal, correlation analysis was performed to identify differentially expressed lncRNAs and immune-related genes. Through receiver operating characteristic analysis, the diagnostic value of specific lncRNAs was identified and evaluated, with a focus on their capacity to distinguish between cancerous and non-cancerous states. The present research revealed 22 differentially expressed lncRNAs and 23 differentially expressed immune-related genes, with 19 immune-related lncRNAs. A total of 13 of these lncRNAs demonstrated diagnostic relevance. In particular, it was demonstrated that the expression of lncRNA CTC-537E7.2 was significantly correlated with patient survival, suggesting its potential as a prognostic marker. Additionally, the expression of lncRNA CTC-537E7.2 was significantly correlated with clinical parameters, such as hormone receptor status and patient demographics. Moreover, it exhibited associations with four distinct immune cell types and demonstrated involvement in the Janus kinase-signal transducer and activator of transcription pathway. Further assessment by in situ hybridization confirmed the increased expression of lncRNA CTC-537E7.2 in samples from HER2+ patients, reinforcing its significance. In summary, the present study uncovered a novel prognostic biomarker for HER2+ breast cancer, thereby laying the groundwork for investigating the underlying molecular mechanisms driving the development of this subtype of breast cancer.

Keywords:  HER2+ breast cancer; TCGA; immune-related predictor; lncRNA; prognostic biomarker

DOI:  https://doi.org/10.3892/ol.2024.14402
Cancer Discov. 2024 Apr 29.

Senescent CAFs mediate immunosuppression and drive breast cancer progression.

Jiayu Ye, John M Baer, Douglas V Faget, Vasilios A Morikis, Qihao Ren, Anupama Melam, Ana Paula Delgado, Xianmin Luo, Satarupa Mullick Bagchi, Jad I Belle, Edward Campos, Michael Friedman, Deborah J Veis, Erik S Knudsen, Agnieszka K Witkiewicz, Scott Powers, Gregory D Longmore, David G DeNardo, Sheila A Stewart.

The tumor microenvironment (TME) profoundly influences tumorigenesis, with gene expression in the breast TME capable of predicting clinical outcomes. The TME is complex and includes distinct cancer-associated fibroblast (CAF) subtypes whose contribution to tumorigenesis remains unclear. Here, we identify a subset of myofibroblast cancer associated fibroblasts (myCAF) that are senescent (senCAF) in mouse and human breast tumors. Utilizing the MMTV-PyMT;INK-ATTAC (INK) mouse model, we found that senCAF-secreted extracellular matrix specifically limits natural killer (NK) cell cytotoxicity to promote tumor growth. Genetic or pharmacologic senCAF elimination unleashes NK cell killing, restricting tumor growth. Finally, we show that senCAFs are present in Her2+, ER+, and triple negative breast cancer and in ductal carcinoma in situ (DCIS) where they predict tumor recurrence. Together, these findings demonstrate that senCAFs are potently tumor promoting and raise the possibility that targeting them by senolytic therapy could restrain breast cancer development.

DOI: https://doi.org/10.1158/2159-8290.CD-23-0426
Zhonghua Bing Li Xue Za Zhi. 2024 May 08. 53(5): 464-469

[Quantitative HER2 mRNA assay in breast cancer with HER2 immunohistochemistry 0].

M C Sun, S F Wu, Y M Cai, Y Y Liu, K M Li, D C Zhao, X Zeng.

Objective: To investigate HER2 mRNA expression in breast cancer with HER2 immunohistochemistry (IHC) 0 and to analyze the feasibility of distinguishing between the tumor with HER2 μltra-low expression and the one without expression of HER2 (no staining by IHC) by HER2 mRNA level preliminarily. Methods: HER2 mRNA was analyzed by reverse transcription digital PCR in 41 cases of formalin-fixed paraffin-embedded surgical tissue samples of invasive breast cancer obtained between January 2020 and March 2023 at Peking Union Medical College Hospital. The cohort included 21 HER2 IHC 1+ and 20 IHC 0 (12 ultra-low and 8 non-expression of HER2). HER2 mRNA expression level was quantitatively evaluated by the FAM (HER2)/VIC (reference gene) ratio. Results: The expression of HER2 mRNA for the cases with 1+, ultra-low, and non-expression of HER2 by IHC was 0.30 to 1.78 (average 0.90, median 0.82), 0.55 to 1.51 (average 0.93, median 0.90) and 0.22 to 0.78 (average 0.41, median 0.36), respectively. For the mean and median HER2 mRNA levels, there was no significant difference between HER2 IHC 1+ and HER2 ultra-low expression diseases (P=0.757). A remarkable difference in HER2 gene expression was found between the tumors with 1+ and non-expression of HER2 by IHC (P=0.002). And, HER2 ultra-low cases contained statistically higher levels of HER2 mRNA compared with non-expression of HER2 subgroup by IHC (P=0.001). Conclusions: Based on HER2 mRNA, HER2 non-expression and HER2 weak expression (including HER2 IHC 1+ and ultra-low) belong to two different types of the tumor and the disease with HER2 IHC 1+ and HER2 ultra-low expression may be the same. It is necessary to further test the performance of HER2 mRNA detection for stratifying the HER2 weak expression subgroup and to determine the threshold.

DOI: https://doi.org/10.3760/cma.j.cn112151-20240125-00063
Malays J Med Sci. 2024 Apr;31(2): 6-17

Systematic Review of Survival Outcomes of Pregnancy-Associated Breast Cancer in Asian Countries.

Syed Sana Abrar, Norsa'adah Bachok.

  Pregnancy-associated breast cancer (PABC) is a rare type of gestational cancer. It poses a significant challenge in diagnosis and management, especially in Asian countries with limited resources. We carried out a systematic literature review and narrative synthesis to identify survival outcomes for women with PABC in Asia. We searched MEDLINE, PubMed, Cochrane Library and the reference lists of the included English language articles for those conducted between January 2010 and August 2022. The search terms were pregnancy-associated breast cancer, breast cancer AND pregnancy, survival of PABC and prognosis of PABC patients. PABC is defined as breast cancer diagnosed either during pregnancy or 1 year-5 years postpartum. This review included observational studies conducted in Asian countries. The final 11 articles met the selection criteria and were analysed. Five of the studies had high quality methods as assessed using the Joanna Briggs Institute (JBI) checklist. We reported study design, year of diagnosis, country, definition of PABC, control group, age of participants, median follow-up time, survival outcomes and pregnancy as prognostic factors. Only five studies reported that PABC patients had a poor overall or disease-free survival rate compared to the control. Pregnancy was a significant independent prognostic factor of breast cancer in only two studies. This review highlights that pregnancy has an unconfirmed association with breast cancer survival in Asia. Most studies that found a non-significant association had small samples, thus there is a need for large-scale multinational epidemiological studies in Asia to establish the survival outcomes in PABC patients.

Keywords:  breast cancer and pregnancy; pregnancy-associated breast cancer; survival outcomes; systematic review

DOI:  https://doi.org/10.21315/mjms2024.31.2.2
Adv Radiat Oncol. 2024 Jun;9(6): 101488

Radiation Therapy for Breast Cancer in Africa.

Rita Oppong, David Yeboah, Mohammed Owusu-Ansah, Samson Pandam Salifu.

Purpose: Although radiation therapy is an effective treatment for breast cancer, it has a low rate of use in African countries. A systematic review was undertaken to investigate studies that used radiation therapy as a treatment modality for patients with breast cancer in Africa, focusing on survival outcomes, adverse effects, radiation therapy techniques, fractionation schedules, and effectiveness of radiation therapy.Methods and Materials: We conducted a comprehensive literature search for studies that treated breast cancer with radiation therapy, using different electronic databases (PubMed, Scopus, and EBSCOhost) up to February 2023. The output was exported to a reference management system for analyses.
Results: The literature search primarily identified 3804 records from Scopus (2427), PubMed (982), and EBSCOhost (395). Based on the inclusion and exclusion criteria, 19 articles were finally included in this systematic review. Most of the studies published were conducted in North Africa (63%), followed by West Africa (21%) and Southeast Africa (16%). Most centers employed external beam radiation therapy to deliver radiation therapy to patients with breast cancer with the standard fractionation size of 50 Gy in 25 fractions. The long-term outcomes with regards to adverse effect suggests that radiation therapy was fairly tolerated among patients with breast cancer.
Conclusions: The reports provide substantial evidence that there are limited number of published studies on the use of radiation therapy for breast cancer treatment in Africa, as well as lower overall survival rate compared with developed countries. To improve breast cancer survivorship, it is necessary for government and other health care planners to provide more radiation therapy resources and implement training programs for personnels.

DOI: https://doi.org/10.1016/j.adro.2024.101488
Cardiooncology. 2024 May 01. 10(1): 27

Endothelial dysfunction in breast cancer survivors on aromatase inhibitors: changes over time.

Adnan Shaaban, Ashley Petersen, Heather Beckwith, Natalia Florea, David A Potter, Douglas Yee, Rachel I Vogel, Daniel Duprez, Anne H Blaes.

  BACKGROUND: Breast cancer is estimated to comprise about 290,560 new cases in 2022. Aromatase inhibitors (AIs) are recommended as adjuvant treatment for estrogen-receptor positive (ER+) breast carcinoma in postmenopausal women, which includes approximately two-thirds of all women with breast cancer. AIs inhibit the peripheral conversion of androgens to estrogen by deactivation of the aromatase enzyme, leading to a reduction in serum estrogen level in postmenopausal women with ER+ breast carcinoma. Estrogen is known for its cardiovascular (CV) protective properties through a variety of mechanisms including vasodilation of blood vessels and inhibition of vascular injury resulting in the prevention of atherosclerosis. In clinical trials and prospective cohorts, the long-term use of AIs can increase the risk for hypertension and hyperlipidemia. Studies demonstrate mixed results as to the impact of AIs on actual CV events and overall survival.METHODS: A single arm longitudinal study of 14 postmenopausal women with ER+ breast cancer prescribed adjuvant AIs at the University of Minnesota (UMN). Subjects with a history of known tobacco use, hypertension, hyperlipidemia, and diabetes were excluded to eliminate potential confounding factors. Participants underwent routine labs, blood pressure assessments, and vascular testing at baseline (prior to starting AIs) and at six months. Vascular assessment was performed using the EndoPAT 2000 and HDI/PulseWave CR-2000 Cardiovascular Profiling System and pulse contour analysis on two occasions as previously described. Vascular measurements were conducted by one trained vascular technician. Assessments were performed in triplicate, and the mean indices were used for analyses. All subjects were on an AI at the follow-up visit. The protocol was approved by the UMN Institutional Review Board and all participants were provided written informed consent. Baseline and follow-up characteristics were compared using Wilcoxon signed-rank tests. Analyses were performed using R version 3.6.1 (R Foundation for Statistical Computing, Vienna, Austria).
RESULTS: After six months of AI treatment, EndoPAT® ratio declined to a median 1.12 (Q1: 0.85, Q3: 1.86; p = 0.045; Figure 1) and median estradiol levels decreased to 2 pg/mL (Q1: 2, Q3: 3; p=0.052). There was no evidence of association between change in EndoPAT® and change in estradiol level (p = 0.91). There were no statistically significant changes in small or large arterial elasticity.
CONCLUSIONS: We hypothesize that long-term use of AI can lead to persistent endothelial dysfunction, and further investigation is necessary. In our study, patients were on AI for approximately 5-10 years. As a result, we do not have data on whether these changes, such as EndoPAT® ratio and the elasticity of small and large arterial, are reversible with discontinuation of AI. These findings set the stage for a larger study to more conclusively determine the association between AI exposure and cardiovascular outcomes. Further studies should evaluate for multivariate associations withmodifiable risk factors for CV disease.

Keywords:  Aromatase inhibitors; Breast cancer; Cardiotoxicity; Endothelial function

DOI:  https://doi.org/10.1186/s40959-024-00227-z
Cell Rep. 2024 May 02. pii: S2211-1247(24)00502-3. [Epub ahead of print]43(5): 114174

Methylation of the chromatin modifier KMT2D by SMYD2 contributes to therapeutic response in hormone-dependent breast cancer.

Ryan Blawski, Bujamin H Vokshi, Xinyu Guo, Srushti Kittane, Mirna Sallaku, Wanlu Chen, Martina Gjyzari, Tony Cheung, Yuhan Zhang, Christopher Simpkins, Weiqiang Zhou, Amanda Kulick, Peihua Zhao, Meihan Wei, Pranavkrishna Shivashankar, Tatiana Prioleau, Pedram Razavi, Richard Koche, Vito W Rebecca, Elisa de Stanchina, Pau Castel, Ho Man Chan, Maurizio Scaltriti, Emiliano Cocco, Hongkai Ji, Minkui Luo, Eneda Toska.

  Activating mutations in PIK3CA are frequently found in estrogen-receptor-positive (ER+) breast cancer, and the combination of the phosphatidylinositol 3-kinase (PI3K) inhibitor alpelisib with anti-ER inhibitors is approved for therapy. We have previously demonstrated that the PI3K pathway regulates ER activity through phosphorylation of the chromatin modifier KMT2D. Here, we discovered a methylation site on KMT2D, at K1330 directly adjacent to S1331, catalyzed by the lysine methyltransferase SMYD2. SMYD2 loss attenuates alpelisib-induced KMT2D chromatin binding and alpelisib-mediated changes in gene expression, including ER-dependent transcription. Knockdown or pharmacological inhibition of SMYD2 sensitizes breast cancer cells, patient-derived organoids, and tumors to PI3K/AKT inhibition and endocrine therapy in part through KMT2D K1330 methylation. Together, our findings uncover a regulatory crosstalk between post-translational modifications that fine-tunes KMT2D function at the chromatin. This provides a rationale for the use of SMYD2 inhibitors in combination with PI3Kα/AKT inhibitors in the treatment of ER+/PIK3CA mutant breast cancer.

Keywords:  AKT; CP: Cancer; CP: Molecular biology; KMT2D; PI3K pathway; SMYD2; alpelisib; breast cancer; chromatin regulation; endocrine therapy; estrogen receptor

DOI:  https://doi.org/10.1016/j.celrep.2024.114174
Pathol Res Pract. 2024 Apr 18. pii: S0344-0338(24)00232-2. [Epub ahead of print]257 155321

Lipoic acid alters the microRNA signature in breast cancer cells.

Hoda Khalife, Mohammad Fayyad-Kazan, Hussein Fayyad-Kazan, Elie Hadchity, Nada Borghol, Nader Hussein, Bassam Badran.

  BACKGROUND: Breast cancer, the deadliest disease affecting women globally, exhibits heterogeneity with distinct molecular subtypes. Despite advances in cancer therapy, the persistence of high mortality rates due to chemotherapy resistance remains a major challenge. Lipoic acid (LA), a natural antioxidant, has proven potent anticancer properties. Yet, the impact of LA on microRNA (miRNA) expression profile in breast cancer remains unexplored.AIM: The aim of this study was to unravel the effect of LA on miRNA expression profiles in different breast cancer cell lines.
METHODS: The MiRCURY LNA miRNA miRNome qPCR Panel was used to compare the miRNA signature in MDA-MB-231 and MCF-7 cells treated or not with LA.
RESULTS: We identified six upregulated and six downregulated miRNAs in LA-treated MDA-MB-231 cells and 14 upregulated and four downregulated miRNAs in LA-treated MCF-7 cells compared to control cells. KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway analysis revealed that the deregulated miRNAs could alter different signaling cascades including FoxO, P53 and Hippo pathways.
CONCLUSION: The outcome of this study provides further insights into the molecular mechanisms underlying the therapeutic benefit of LA. This in turn could assist the amelioration of LA-based anticancer therapies.

Keywords:  Breast cancer; Lipoic acid; MicroRNA

DOI:  https://doi.org/10.1016/j.prp.2024.155321
Biotechnol Appl Biochem. 2024 Apr 30.

Synergistic effects of miR-143 with miR-99a inhibited cell proliferation and induced apoptosis in breast cancer.

Zahra Doosti, Syed Omar Ebrahimi, Mahshid Samie Ghahfarokhi, Somayeh Reiisi.

  Breast cancer (BC) is the most common cancer type and the fifth leading cause of cancer-related deaths. The primary goals of BC treatment are to remove the tumor and prevent metastasis. Despite advances in BC treatment, more effective therapies are required. miRNAs can regulate many targets involved in biological processes and tumor progression; these molecules have emerged as a promising cancer treatment strategy. In the present study, we investigated the effects of miR-99a and miR-143 in single expression plasmids for BC inhibition. In this study, the precursor structure of miRNAs in the expression vector pEGFP-N1 entered single and double states, and MCF7 and T47D cells were transfected. The miRNAs expression level after transfection was then measured using qPCR. The MultiMiR package was used to obtain predicted and validated miRNA targets. MTT assay, qRT-PCR, migration test, and flow cytometry were used to assess the effect of miRNA and gene modulation. The qPCR results revealed that miRNA constructs were significantly expressed after the transfection of both cell lines. The biological function of miRNAs showed that upregulation of miR-99a and miR-143 in any of the two selected BC cells inhibited their proliferation and migration rate, significantly inducing apoptosis (p < 0.01). Also, miR-99a/miR-143 co-treatment has a synergistic anticancer effect in cancer cells via Akt1 and CDK6 targeting. These findings suggest that miR-99a/miR-143 plays synergistic regulatory roles in BC, possibly via a shared signaling pathway, providing a therapeutic strategy for BC treatment.

Keywords:  apoptosis; breast cancer; miRNA‐143; miR‐99a; synergism effect

DOI:  https://doi.org/10.1002/bab.2592
Cell Mol Biol (Noisy-le-grand). 2024 Apr 28. 70(4): 242-247

Correlation of IDH1 gene expression error in breast tumor biopsy in patients with invasive ductal carcinoma.

Behzad Rostami, Sepehr Kahrizi, Batool Ghorbani Yekta, Rezvan Ghadyani, Aliasghar Keramatinia, Seyed Jalil Hoseini, Saeed Karima, Abdol Rahim Nikzamir, Neda Mansouri, Muzi Chen, Abolfazl Movafagh.

One of the most important cancers in terms of worldwide prevalence is breast tumors, which have been less investigated in correlation with the enzyme Isocitrate Dehydrogenase 1 (IDH1) gene. The aim of this study was that expression of this gene could have significant effects on the progression of metastasis and invasive disease in breast cancer patients. We used the molecular method of RT-PCR with SYBR-Green to analyze breast tumor tissue from patients with metastasis and non-metastasis, the latter confirmed by the pathology department of Shohada-e Tajrish Hospital (serving as a control group). Also, patients population and its relationship with the degree of tumor in the IDH1 gene was investigated. The IDH1 gene has shown high expression in patients with metastatic breast cancer rather than in patients with non-metastatic breast cancer. The metastatic samples were compared with non-metastatic samples for IDH1 mRNA expression. In this research work, 72.5% (29 samples) were up-regulated in comparison to 27.5% of samples (11 samples) that did not exhibit high expression (P=0.000). This study examined the IDH1 gene expression, suggesting that changes in this gene's expression could impact the prognosis of breast cancer. However, further research is needed to draw definitive conclusions.

DOI: https://doi.org/10.14715/cmb/2024.70.4.38
Oncol Res. 2024 ;32(5): 943-953

Metochalcone induces senescence-associated secretory phenotype via JAK2/STAT3 pathway in breast cancer.

Jianbo Zhou, Feng Wan, Bin Xiao, Xin Li, Cheng Peng, F U Peng.

  Breast and lung cancers are the leading causes of mortality and most frequently diagnosed cancers in women and men, respectively, worldwide. Although the antitumor activity of chalcones has been extensively studied, the molecular mechanisms of isoliquiritigenin analog 2', 4', 4-trihydroxychalcone (metochalcone; TEC) against carcinomas remain less well understood. In this study, we found that TEC inhibited cell proliferation of breast cancer BT549 cells and lung cancer A549 cells in a concentration-dependent manner. TEC induced cell cycle arrest in the S-phase, cell migration inhibition in vitro, and reduced tumor growth in vivo. Moreover, transcriptomic analysis revealed that TEC modulated the activity of the JAK2/STAT3 and P53 pathways. TEC triggered the senescence-associated secretory phenotype (SASP) by repressing the JAK2/STAT3 axis. The mechanism of metochalcone against breast cancer depended on the induction of SASP via deactivation of the JAK2/STAT3 pathway, highlighting the potential of chalcone in senescence-inducing therapy against carcinomas.

Keywords:  Breast cancer; JAK2/STAT3; Lung cancer; Metochalcone; SASP

DOI:  https://doi.org/10.32604/or.2023.044775