bims-merabr 2024-05-12 papers

bims-merabr

Biomed News

on Metabolic rewiring in aggressive breast cancer

Issue of 2024‒05‒12
nineteen papers selected by
Barbara Mensah Sankofi, University of Oklahoma Health Sciences Center

MEIS2 suppresses breast cancer development by downregulating IL10.
LHPP expression in triple-negative breast cancer promotes tumor growth and metastasis by modulating the tumor microenvironment.
Identification of Breast Cancer Subtypes Based on Endoplasmic Reticulum Stress-Related Genes and Analysis of Prognosis and Immune Microenvironment in Breast Cancer Patients.
Berberine inhibits the progression of breast cancer by regulating METTL3-mediated m6A modification of FGF7 mRNA.
Overexpressing S100A9 ameliorates NK cell dysfunction in estrogen receptor-positive breast cancer.
Ciliogenesis-associated Kinase 1 Promotes Breast Cancer Cell Proliferation and Chemoresistance via Phosphorylating ERK1.
MICAL-L2, as an estrogen-responsive gene, is involved in ER-positive breast cancer cell progression and tamoxifen sensitivity via the Akt/mTOR pathway.
TRPV3 regulates Breast Cancer Cell Proliferation and Apoptosis by EGFR/AKT pathway.
Interrogating Estrogen Signaling Pathways in Human ER-Positive Breast Cancer Cells Forming Bone Metastases in Mice.
LncRNA LINC00466 Promotes the Progression of Breast Cancer via miR-4731-5p/EPHA2 Pathway.
E3 ubiquitin ligase BCA2 promotes breast cancer stemness by up-regulation of SOX9 by LPS.
Identification of the new molecular subtypes related to inflammation in breast cancer.
TRIM58 downregulation maintains stemness via MYH9-GRK3-YAP axis activation in triple-negative breast cancer stem cells.
PD-L1 intrinsically promotes the proliferation of breast cancer cells through the SKP2-p27/p21 axis.
miRNA-200c-3p deficiency promotes epithelial-mesenchymal transition in triple-negative breast cancer by activating CRKL expression.
Polyphyllin VII Promotes Apoptosis in Breast Cancer by Inhibiting MAPK/ERK Signaling Pathway through Downregulation of SOS1.
Epigenetic Modulations in Triple-Negative Breast Cancer: Therapeutic Implications for Tumor Microenvironment.
SOX13 is a novel prognostic biomarker and associates with immune infiltration in breast cancer.
Heat shock protein 72 supports extracellular matrix production in metastatic mammary tumors.

Cancer Rep (Hoboken). 2024 May;7(5): e2064

MEIS2 suppresses breast cancer development by downregulating IL10.

Yongzhi Xiao, Yingzhe Liu, Yangqing Sun, Changhao Huang, Shangwei Zhong.

  BACKGROUND: Breast cancer (BC) is the most commonly diagnosed female cancer. Homeobox protein MEIS2, a key transcription factor, is involved in the regulation of many developmental and cellular processes. However, the role of MEIS2 in the development of breast cancer is still unclear.AIMS: We aimed to examine the role of myeloid ecotropic insertion site (MEIS2) in breast cancer and the association of MEIS2 with breast cancer clinical stages and pathological grades. We revealed the underlying mechanism by which MEIS2 affected breast cancer cell growth and tumor development.
METHODS AND RESULTS: Using human BC cell lines, clinical samples and animal xenograft model, we reveal that MEIS2 functions as a tumor suppressor in breast cancer. The expression of MEIS2 is inversely correlated with BC clinical stages and pathological grades. MEIS2 knockdown (MEIS2-KD) promotes while MEIS2 overexpression suppresses breast cancer cell proliferation and tumor development in vitro and in animal xenograft models, respectively. To determine the biological function of MEIS2, we screen the expression of a group of MEIS2 potential targeting genes in stable-established cell lines. Results show that the knockdown of MEIS2 in breast cancer cells up-regulates the IL10 expression, but MEIS2 overexpression opposed the effect on IL10 expression. Furthermore, the suppressive role of MEIS2 in breast cancer cell proliferation is associated with the IL10 expression and myeloid cells infiltration.
CONCLUSION: Our study demonstrates that the tumor suppressor of MEIS2 in breast cancer progression is partially via down regulating the expression of IL10 and promoting myeloid cells infiltration. Targeting MEIS2 would be a potentially therapeutic avenue for BC.

Keywords:  IL10; MEIS2; breast cancer; myeloid cells

DOI:  https://doi.org/10.1002/cnr2.2064
bioRxiv. 2024 Apr 23. pii: 2024.04.19.590151. [Epub ahead of print]

LHPP expression in triple-negative breast cancer promotes tumor growth and metastasis by modulating the tumor microenvironment.

Jeffrey Reina, Queralt Vallmajo-Martin, Jia Ning, Aubrey N Michi, Kay Yeung, Geoffrey M Wahl, Tony Hunter.

Triple-negative breast cancer (TNBC) is a highly aggressive and metastatic form of breast cancer that lacks an effective targeted therapy. To identify new therapeutic targets, we investigated the phosphohistidine phosphatase, LHPP, which has been implicated in the development of several types of cancer. However, the full significance of LHPP in cancer progression remains unclear due to our limited understanding of its molecular mechanism. We found that levels of the LHPP phosphohistidine phosphatase were significantly increased in human breast cancer patients compared to normal adjacent tissues, with the highest levels in the TNBC subtype. When LHPP was knocked out in the MDA-MB-231 human TNBC cell line, cell proliferation, wound healing capacity, and invasion were significantly reduced. However, LHPP knockout in TNBC cells did not affect the phosphohistidine protein levels. Interestingly, LHPP knockout in MDA-MB-231 cells delayed tumor growth and reduced metastasis when orthotopically transplanted into mouse mammary glands. To investigate LHPP's role in breast cancer progression, we used next-generation sequencing and proximity-labeling proteomics, and found that LHPP regulates gene expression in chemokine-mediated signaling and actin cytoskeleton organization. Depletion of LHPP reduced the presence of tumor-infiltrating macrophages in mouse xenografts. Our results uncover a new tumor promoter role for LHPP phosphohistidine phosphatase in TNBC and suggest that targeting LHPP phosphatase could be a potential therapeutic strategy for TNBC.

DOI: https://doi.org/10.1101/2024.04.19.590151
Technol Cancer Res Treat. 2024 Jan-Dec;23:23 15330338241241484

Identification of Breast Cancer Subtypes Based on Endoplasmic Reticulum Stress-Related Genes and Analysis of Prognosis and Immune Microenvironment in Breast Cancer Patients.

Chen Yi, Jun Yang, Ting Zhang, Liu Qin, Dongjuan Chen.

  Introduction: Endoplasmic reticulum stress (ERS) was a response to the accumulation of unfolded proteins and plays a crucial role in the development of tumors, including processes such as tumor cell invasion, metastasis, and immune evasion. However, the specific regulatory mechanisms of ERS in breast cancer (BC) remain unclear. Methods: In this study, we analyzed RNA sequencing data from The Cancer Genome Atlas (TCGA) for breast cancer and identified 8 core genes associated with ERS: ELOVL2, IFNG, MAP2K6, MZB1, PCSK6, PCSK9, IGF2BP1, and POP1. We evaluated their individual expression, independent diagnostic, and prognostic values in breast cancer patients. A multifactorial Cox analysis established a risk prognostic model, validated with an external dataset. Additionally, we conducted a comprehensive assessment of immune infiltration and drug sensitivity for these genes. Results: The results indicate that these eight core genes play a crucial role in regulating the immune microenvironment of breast cancer (BRCA) patients. Meanwhile, an independent diagnostic model based on the expression of these eight genes shows limited independent diagnostic value, and its independent prognostic value is unsatisfactory, with the time ROC AUC values generally below 0.5. According to the results of logistic regression neural networks and risk prognosis models, when these eight genes interact synergistically, they can serve as excellent biomarkers for the diagnosis and prognosis of breast cancer patients. Furthermore, the research findings have been confirmed through qPCR experiments and validation. Conclusion: In conclusion, we explored the mechanisms of ERS in BRCA patients and identified 8 outstanding biomolecular diagnostic markers and prognostic indicators. The research results were double-validated using the GEO database and qPCR.

Keywords:  breast cancer; endoplasmic reticulum stress; immune features; machine learning approach; prognosis

DOI:  https://doi.org/10.1177/15330338241241484
Thorac Cancer. 2024 May 06.

Berberine inhibits the progression of breast cancer by regulating METTL3-mediated m6A modification of FGF7 mRNA.

Wei Fu, Lixin Liu, Suiju Tong.

  BACKGROUND: Berberine (BBR), an isoquinoline alkaloid from Coptidis rhizoma, has been found to have powerful activities against various human malignancies, including breast cancer. However, the underlying antitumor mechanisms of BBR in breast cancer remain poorly understood.METHODS: Breast cancer cells were cultured and treated with different doses (0, 20, 40, and 60 μM) of BBR for 48 h. Cell viability, proliferation, apoptosis, invasion, and migration were assessed using 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2H-tetrazolium bromide (MTT), 5-ethynyl-2'-deoxyuridine (EdU), flow cytometry, transwell, and wound healing assays. Fibroblast growth factor 7 (FGF7), methyltransferase-like 3 (METTL3), and insulin-like growth factor-2 mRNA-binding protein 3 (IGF2BP3) mRNA levels and protein levels were measured using real-time quantitative polymerase chain reaction (RT-qPCR) and western blot. Interaction between METTL3 and FGF7 m6A was assessed using methylated RNA immunoprecipitation (MeRIP)-qPCR and RNA immunoprecipitation (RIP) assay. Binding ability between IGF2BP3 and FGF7 mRNA was analyzed using RIP assay.
RESULTS: BBR treatment hindered breast cancer cell proliferation, invasion, migration, and induced apoptosis. FGF7 expression was upregulated in breast cancer tissues, while its level was reduced in BBR-treated tumor cells. FGF7 upregulation relieved the repression of BBR on breast cancer cell malignant behaviors. In mechanism, METTL3 stabilized FGF7 mRNA through the m6A-IGF2BP3-dependent mechanism and naturally improved FGF7 expression. BBR treatment inhibited breast cancer growth in vivo.
CONCLUSION: BBR treatment blocked breast cancer cell growth and metastasis partly by regulating METTL3-mediated m6A modification of FGF7 mRNA, providing a promising therapeutic target for breast cancer treatment.

Keywords:  BBR; FGF7; IGF2BP3; METTL3; breast cancer

DOI:  https://doi.org/10.1111/1759-7714.15321
Cancer Immunol Immunother. 2024 May 07. 73(7): 117

Overexpressing S100A9 ameliorates NK cell dysfunction in estrogen receptor-positive breast cancer.

Yansong Liu, Mingcui Li, Zhengbo Fang, Shan Gao, Weilun Cheng, Yunqiang Duan, Xuelian Wang, Jianyuan Feng, Tianshui Yu, Jiarui Zhang, Ting Wang, Anbang Hu, Hanyu Zhang, Zhiyuan Rong, Suborna S Shakila, Yuhang Shang, Fanjing Kong, Jiangwei Liu, Yanling Li, Fei Ma.

  BACKGROUND: Estrogen receptor (ER) positive human epidermal growth factor receptor 2 (HER2) negative breast cancer (ER+/HER2-BC) and triple-negative breast cancer (TNBC) are two distinct breast cancer molecular subtypes, especially in tumor immune microenvironment (TIME). The TIME of TNBC is considered to be more inflammatory than that of ER+/HER2-BC. Natural killer (NK) cells are innate lymphocytes that play an important role of tumor eradication in TME. However, studies focusing on the different cell states of NK cells in breast cancer subtypes are still inadequate.METHODS: In this study, single-cell mRNA sequencing (scRNA-seq) and bulk mRNA sequencing data from ER+/HER2-BC and TNBC were analyzed. Key regulator of NK cell suppression in ER+/HER2-BC, S100A9, was quantified by qPCR and ELISA in MCF-7, T47D, MDA-MB-468 and MDA-MB-231 cell lines. The prognosis predictability of S100A9 and NK activation markers was evaluated by Kaplan-Meier analyses using TCGA-BRAC data. The phenotype changes of NK cells in ER+/HER2-BC after overexpressing S100A9 in cancer cells were evaluated by the production levels of IFN-gamma, perforin and granzyme B and cytotoxicity assay.
RESULTS: By analyzing scRNA-seq data, we found that multiple genes involved in cellular stress response were upregulated in ER+/HER2-BC compared with TNBC. Moreover, TLR regulation pathway was significantly enriched using differentially expressed genes (DEGs) from comparing the transcriptome data of ER+/HER2-BC and TNBC cancer cells, and NK cell infiltration high/low groups. Among the DEGs, S100A9 was identified as a key regulator. Patients with higher expression levels of S100A9 and NK cell activation markers had better overall survival. Furthermore, we proved that overexpression of S100A9 in ER+/HER2-cells could improve cocultured NK cell function.
CONCLUSION: In conclusion, the study we presented demonstrated that NK cells in ER+/HER2-BC were hypofunctional, and S100A9 was an important regulator of NK cell function in ER+BC. Our work contributes to elucidate the regulatory networks between cancer cells and NK cells and may provide theoretical basis for novel drug development.

Keywords:  Breast cancer; NK cell; S100A9; Tumor microenvironment

DOI:  https://doi.org/10.1007/s00262-024-03699-1
Int J Biol Sci. 2024 ;20(7): 2403-2421

Ciliogenesis-associated Kinase 1 Promotes Breast Cancer Cell Proliferation and Chemoresistance via Phosphorylating ERK1.

Yanling He, Xinyuan Zhang, Weijun Pan, Jiebiao Zhang, Weiliang Zhu, Jian Zhang, Jian Shi.

  Ciliogenesis-associated kinase 1 (CILK1) plays a key role in the ciliogenesis and ciliopathies. It remains totally unclear whether CILK1 is involved in tumor progression and therapy resistance. Here, we report that the aberrant high-expression of CILK1 in breast cancer is required for tumor cell proliferation and chemoresistance. Two compounds, CILK1-C30 and CILK1-C28, were identified with selective inhibitory effects towards the Tyr-159/Thr-157 dual-phosphorylation of CILK1, pharmacological inhibition of CILK1 significantly suppressed tumor cell proliferation and overcame chemoresistance in multiple experimental models. Large-scale screen of CILK1 substrates confirmed that the kinase directly phosphorylates ERK1, which is responsible for CILK1-mediated oncogenic function. CILK1 is also indicated to be responsible for the chemoresistance of small-cell lung cancer cells. Our data highlight the importance of CILK1 in cancer, implicating that targeting CILK1/ERK1 might offer therapeutic benefit to cancer patients.

Keywords:  Breast cancer; CILK1; Chemoresistance; ERK1; Proliferation

DOI:  https://doi.org/10.7150/ijbs.87442
Biochem Pharmacol. 2024 May 08. pii: S0006-2952(24)00239-9. [Epub ahead of print] 116256

MICAL-L2, as an estrogen-responsive gene, is involved in ER-positive breast cancer cell progression and tamoxifen sensitivity via the Akt/mTOR pathway.

Pushuai Wen, Jing Li, Zihao Wen, Xiaoyan Guo, Guoqun Ma, Shuzhen Hu, Jiamei Xu, Hongli Zhao, Ruixin Li, Ying Liu, Yu Wang, Jing Gao.

  Endocrine treatment, particularly tamoxifen, has shown significant improvement in the prognosis of patients with estrogen receptor-positive (ER-positive) breast cancer. However, the clinical utility of this treatment is often hindered by the development of endocrine resistance. Therefore, a comprehensive understanding of the underlying mechanisms driving ER-positive breast cancer carcinogenesis and endocrine resistance is crucial to overcome this clinical challenge. In this study, we investigated the expression of MICAL-L2 in ER-positive breast cancer and its impact on patient prognosis. We observed a significant upregulation of MICAL-L2 expression in ER-positive breast cancer, which correlated with a poorer prognosis in these patients. Furthermore, we found that estrogen-ERβ signaling promoted the expression of MICAL-L2. Functionally, our study demonstrated that MICAL-L2 not only played an oncogenic role in ER-positive breast cancer tumorigenesis but also influenced the sensitivity of ER-positive breast cancer cells to tamoxifen. Mechanistically, as an estrogen-responsive gene, MICAL-L2 facilitated the activation of the Akt/mTOR signaling pathway in ER-positive breast cancer cells. Collectively, our findings suggest that MICAL-L2 could serve as a potential prognostic marker for ER-positive breast cancer and represent a promising molecular target for improving endocrine treatment and developing therapeutic approaches for this subtype of breast cancer.

Keywords:  Breast cancer; Endocrine therapy; Estrogen receptor; MICAL-L2; Tamoxifen

DOI:  https://doi.org/10.1016/j.bcp.2024.116256
J Cancer. 2024 ;15(10): 2891-2899

TRPV3 regulates Breast Cancer Cell Proliferation and Apoptosis by EGFR/AKT pathway.

Yan Xie, Hyo In Kim, Qianzhi Yang, Jinghao Wang, Wei Huang.

  Breast cancer (BC) is one of the most common cancer types worldwide and the first cause of cancer-related deaths in women. Transient receptor potential vanillin 3 (TRPV3) has been preliminarily discovered to play an important role in various cancers, including BC. Here, we explored the effect of TRPV3 on breast cancer cells and its potential mechanism. TRPV3 level was measured in BC tissue and adjacent noncancerous breast tissue using real-time RT-PCR and Western blot. Wound healing was used to detect cell migration. MTT and EDU were detected cell proliferation. TUNEL and Caspase-3 activity were used to detect cell apoptosis. We found that TRPV3 expression significantly increased in both human BC tissues and breast cells line. TRPV3 siRNA (TRPV3 inhibition) dramatically suppressed cell migration and proliferation, promoted the apoptosis, and decreased [Ca2+]i; whereas Carvacrol (TRPV3 agonist) has opposite effect in MCF-7 cells. We validated EGFR (Epidermal growth factor receptor) is a direct target protein of TRPV3. Mechanism studies have shown that Carvacrol increased phosphorylation levels of EGFR and AKT, and were decreased by suppression of TRPV3. Moreover, Erlotinib (EGFR inhibitor) and LY294002 (PI3K inhibitor) diminished Carvacrol induced cell migration and proliferation, promoted cell apoptosis, and increased [Ca2+]i in Carvacrol group. Our results collectively suggest that TRPV3 siRNA inhibits migration and proliferation, and promoted apoptosis in breast cancer cells by EGFR/AKT pathway. These findings indicate that TRPV3 may represent a novel therapeutic strategy for breast cancer.

Keywords:  EGFR; TRPV3; apoptosis; breast cancer; proliferation

DOI:  https://doi.org/10.7150/jca.93940
Endocrinology. 2024 Apr 29. pii: bqae038. [Epub ahead of print]165(6):

Interrogating Estrogen Signaling Pathways in Human ER-Positive Breast Cancer Cells Forming Bone Metastases in Mice.

Julia N Cheng, Jennifer B Frye, Susan A Whitman, Sima Ehsani, Simak Ali, Janet L Funk.

  Breast cancer bone metastases (BMET) are incurable, primarily osteolytic, and occur most commonly in estrogen receptor-α positive (ER+) breast cancer. ER+ human breast cancer BMET modeling in mice has demonstrated an estrogen (E2)-dependent increase in tumor-associated osteolysis and bone-resorbing osteoclasts, independent of estrogenic effects on tumor proliferation or bone turnover, suggesting a possible mechanistic link between tumoral ERα-driven osteolysis and ER+ bone progression. To explore this question, inducible secretion of the osteolytic factor, parathyroid hormone-related protein (PTHrP), was utilized as an in vitro screening bioassay to query the osteolytic potential of estrogen receptor- and signaling pathway-specific ligands in BMET-forming ER+ human breast cancer cells expressing ERα, ERß, and G protein-coupled ER. After identifying genomic ERα signaling, also responsibility for estrogen's proliferative effects, as necessary and sufficient for osteolytic PTHrP secretion, in vivo effects of a genomic-only ER agonist, estetrol (E4), on osteolytic ER+ BMET progression were examined. Surprisingly, while pharmacologic effects of E4 on estrogen-dependent tissues, including bone, were evident, E4 did not support osteolytic BMET progression (vs robust E2 effects), suggesting an important role for nongenomic ER signaling in ER+ metastatic progression at this site. Because bone effects of E4 did not completely recapitulate those of E2, the relative importance of nongenomic ER signaling in tumor vs bone cannot be ascertained here. Nonetheless, these intriguing findings suggest that targeted manipulation of estrogen signaling to mitigate ER+ metastatic progression in bone may require a nuanced approach, considering genomic and nongenomic effects of ER signaling on both sides of the tumor/bone interface.

Keywords:  bone metastases; breast cancer; estetrol; estradiol; estrogen receptor-alpha; nongenomic

DOI:  https://doi.org/10.1210/endocr/bqae038
Curr Pharm Biotechnol. 2024 May 09.

LncRNA LINC00466 Promotes the Progression of Breast Cancer via miR-4731-5p/EPHA2 Pathway.

Xue Han, Fan Shi, Shujun Guo, Yao Li, Hongtao Wang, Chuanwang Song, Shiwu Wu.

 BACKGROUND: Breast Cancer (BC) is a female malignancy with a high mortality rate. Novel diagnostic and prognostic biomarkers are valuable for reducing BC mortality. Our study is designed to undrape the precise role of the LINC00466/miR-4731-5p/EPHA2 axis in BC. Methods: The Cancer Genome Atlas (TCGA) sequencing dataset was utilized to compare the levels of LINC00466. The levels of LINC00466, miR-4731-5p, and EPHA2 were tested by qRTPCR. Cell proliferation and cycle were detected by CCK-8 assay and flow cytometer. In vivo role of LINC00466 was tested by Xenograft nude models. Binding sites were predicted by TargetScan and Starbase. The binding relationship was employed by Dual-luciferase reporter gene assay and RNA pull-down assay. Results: LINC00466 was increased in human breast cancer tissues. LINC00466 was negatively associated with miR-4731-5p and positively correlated with EPHA2 in human breast cancer tissues. Down-regulation of LINC00466 suppressed the proliferation and arrested the cell cycle of breast cancer cells, and inhibited tumor growth in vivo. Conclusion: LINC00466 promoted BC development via mediating the miR-4731-5p/EPHA2 axis, which has the potential value as a promising therapeutic target in BC.

Keywords: Breast cancer; EPHA2.; LINC00466; miR-4731-5p

DOI: https://doi.org/10.2174/0113892010290582240419051056
Int J Biol Sci. 2024 ;20(7): 2686-2697

E3 ubiquitin ligase BCA2 promotes breast cancer stemness by up-regulation of SOX9 by LPS.

Min Zheng, Wenjing Liu, Rou Zhang, Dewei Jiang, Yujie Shi, Yingying Wu, Fei Ge, Ceshi Chen.

  Triple-negative breast cancer (TNBC) is the most malignant subtype of breast cancer. Breast cancer stem cells (BCSCs) are believed to play a crucial role in the carcinogenesis, therapy resistance, and metastasis of TNBC. It is well known that inflammation promotes stemness. Several studies have identified breast cancer-associated gene 2 (BCA2) as a potential risk factor for breast cancer incidence and prognosis. However, whether and how BCA2 promotes BCSCs has not been elucidated. Here, we demonstrated that BCA2 specifically promotes lipopolysaccharide (LPS)-induced BCSCs through LPS induced SOX9 expression. BCA2 enhances the interaction between myeloid differentiation primary response protein 88 (MyD88) and Toll-like receptor 4 (TLR4) and inhibits the interaction of MyD88 with deubiquitinase OTUD4 in the LPS-mediated NF-κB signaling pathway. And SOX9, an NF-κB target gene, mediates BCA2's pro-stemness function in TNBC. Our findings provide new insights into the molecular mechanisms by which BCA2 promotes breast cancer and potential therapeutic targets for the treatment of breast cancer.

Keywords:  BCA2; Breast cancer stem cells; LPS; MyD88; SOX9

DOI:  https://doi.org/10.7150/ijbs.92338
Medicine (Baltimore). 2024 May 10. 103(19): e38146

Identification of the new molecular subtypes related to inflammation in breast cancer.

Ke Yu, Chi Xu, Feng Wang, Hua Wang.

Breast cancer is a prevalent ailment among women, and the inflammatory response plays a crucial role in the management and prediction of breast cancer (BRCA). However, the new subtypes based on inflammation in BRCA research are still undefined. The databases including The Cancer Genome Atlas and gene expression omnibus were utilized to gather clinical data and somatic mutation information for approximately 1069 BRCA patients. Through Consensus Clustering, novel subtypes linked to inflammation were identified. A comparative analysis was conducted on the prognosis, and immune cell infiltration, and somatic mutation of the new subtypes. Additionally, an investigation into drug therapy and immunotherapy was conducted to distinguish high-risk individuals from low-risk ones. The findings of this investigation proposed the categorization of BRCA into innovative subtypes predicated on the inflammatory response and 6 key genes were a meaningful approach. Specifically, the low-, medium-, and high-inflammation subtypes exhibited varying degrees of association with clinicopathological features, tumor microenvironment, and prognosis. Notably, the high-inflammation subtype was characterized by a strong correlation with immunosuppressive microenvironments and a higher frequency of somatic mutations, which was an indication of poorer health. This study revealed that a brand-new classification could throw new light on the effective prognosis. The integration of multiple key genes was a new characterization that could promote more immunotherapy strategies and contribute to predicting the efficacy of the chemotherapeutic drugs.

DOI: https://doi.org/10.1097/MD.0000000000038146
Cancer Gene Ther. 2024 May 07.

TRIM58 downregulation maintains stemness via MYH9-GRK3-YAP axis activation in triple-negative breast cancer stem cells.

Xujun Li, Jing Jiang, Qian Wu, Tianzi You, Fan Yang.

TRIM58 is a member of the TRIM protein family, which possess with E3 ubiquitin ligase activities. Studies have revealed that low expression of TRIM58 plays key roles, has been implicated in the tumor progression of tumor formation due to its reduced expression. However, its role in regulating the stemness of breast cancer stem cells (CSCs) remains unexplored. Here, we found that TRIM58 was underexpressed in TNBC tissues and cells compared to adjacent mucosa tissue, and its downregulation was significantly associated with shorter survival. Overexpression of TRIM58 reduced the proportion of CD44 + /CD24- cells, upregulated differentiation genes, and inhibited stemness-related gene expression in TNBC CSCs. In vitro and in vivo experiments revealed that TRIM58 overexpression in CSCs suppressed tumor sphere formation and tumorigenic capacity. Co-IP results indicated direct interaction between TRIM58 and MYH9, with TRIM58 inducing MYH9 degradation via ubiquitination in differentiated cells. Label-free quantitative proteomics identified GRK3 and Hippo-YAP as downstream targets and signaling pathways of MYH9. TIMER database analysis, immunohistochemistry, western blotting, DNA-protein pulldown experiments, and dual luciferase reporter assays demonstrated that MYH9 regulated GRK3 transcriptional activation in CSCs. In conclusion, elevated TRIM58 expression in CSCs downregulates MYH9 protein levels by promoting ubiquitin-mediated degradation, thereby inhibiting downstream GRK3 transcription, inactivating the YAP stemness pathway, and ultimately promoting CSC differentiation.

DOI: https://doi.org/10.1038/s41417-024-00780-w
Cancer Cell Int. 2024 May 09. 24(1): 161

PD-L1 intrinsically promotes the proliferation of breast cancer cells through the SKP2-p27/p21 axis.

Marwa Elfoly, Jumanah Y Mirza, Ayodele Alaiya, Amal A Al-Hazzani, Asma Tulbah, Monther Al-Alwan, Hazem Ghebeh.

 BACKGROUND: PD-L1 intrinsically promotes tumor progression through multiple mechanisms, which potentially leads to resistance to anti-PD-1/PD-L1 therapies. The intrinsic effect of PD-L1 on breast cancer (BC) cell proliferation has not been fully elucidated.METHODS: we used proteomics, gene expression knockdown (KD), quantitative immunofluorescence (qIF), western blots, functional assays including colony-forming assay (CFA) and real-time cell analyzer (RTCA), and in vivo data using immunohistochemistry in breast cancer patients.
RESULTS: PD-L1 promoted BC cell proliferation by accelerating cell cycle entry at the G1-to-S phase transition. Global proteomic analysis of the differentially expressed nuclear proteins indicated the involvement of several proliferation-related molecules, including p21CIP1/WAF1. Western blotting and qIF demonstrated the higher expression of SKP2 and the lower expression of p21CIP1/WAF1 and p27Kip1 in PD-L1 expressing (PD-L1pos) cells as compared to PD-L1 KD (PD-L1KD) cells. Xenograft-derived cells and the TCGA BC dataset confirmed this relationship in vivo. Functionally, CFA and RTCA demonstrated the central role of SKP2 in promoting PD-L1-mediated proliferation. Finally, immunohistochemistry in 74 breast cancer patients confirmed PD-L1 and SKP-p21/p27 axis relationship, as it showed a highly statistically significant correlation between SKP2 and PD-L1 expression (p < 0.001), and both correlated significantly with the proliferation marker Ki-67 (p < 0.001). On the other hand, there was a statistically significant inverse relationship between PD-L1 and p21CIP1/WAF1 expression (p = 0.005). Importantly, double negativity for p21CIP1/WAF1 and p27Kip1 correlated significantly with PD-L1 (p < 0.001), SKP2 (p = 0.002), and Ki-67 (p = 0.002).
CONCLUSIONS: we have demonstrated the role of the SKP2-p27/p21 axis in intrinsic PD-L1-enhanced cell cycle progression. Inhibitors of SKP2 expression can alleviate resistance to ICPIs.

Keywords: PD-L1; Proliferation; SKP2; p21; p27

DOI: https://doi.org/10.1186/s12935-024-03354-w
Discov Oncol. 2024 May 08. 15(1): 146

miRNA-200c-3p deficiency promotes epithelial-mesenchymal transition in triple-negative breast cancer by activating CRKL expression.

Fangfang Nie, Qinfang Zhang, WeiNa Ma, Jun Yan.

  Epithelial-mesenchymal transition (EMT) plays an important role in malignant progression of Triple-negative breast cancer (TNBC). Many studies have confirmed that miRNA-200c-3p is related to EMT. And we found that it is involved in the regulation of EMT, but the exact mechanism is unclear. CRKL is highly expressed in a variety of tumors and plays a role in EMT. In this study, the potential targets of miRNA-200c-3p were searched in miRPathDB, Targetscan and PicTar. And there are 68 potential targets at the intersection of the three databases. Then, bioinformatics and text mining performed by Coremine Medica, and found that among 68 potential targets, CRKL has the strongest correlation with EMT in TNBC. Therefore, we speculated that miRNA-200c-3p involvement in EMT might be related to CRKL. To verify miRNA-200c-3p inhibits the malignant phenotype of TNBC by regulating CRKL, RT‒PCR, western blotting, Clonal formation assays,CCK-8 proliferation assays, transwell invasion assays, Luciferase reporter assay and nude mouse transplantation tumor assay were performed. In this study, we found that miRNA-200c-3p is under-expressed and EMT-related genes are up-regulated in TNBC, and miRNA-200c-3p can inhibit cancer cell proliferation, invasion and the expression of EMT-related genes and proteins in TNBC. Further research confirmed that miRNA-200c-3p could inhibit EMT by inhibiting the expression of CRKL that directly combining CRKL gene.

Keywords:  CRKL; Epithelial-mesenchymal transition; Malignant phenotype; Triple-negative breast cancer

DOI:  https://doi.org/10.1007/s12672-024-01004-1
Am J Chin Med. 2024 May 08. 1-20

Polyphyllin VII Promotes Apoptosis in Breast Cancer by Inhibiting MAPK/ERK Signaling Pathway through Downregulation of SOS1.

Shu-Guang Du, Hua-Min Zhang, Yun-Xia Ji, Yu-Lin Tian, Dan Wang, Kun Zhu, Qing-Gao Zhang, Shuang-Ping Liu.

  Polyphyllin VII is a biologically active herbal monomer extracted from the traditional Chinese herbal medicine Chonglou. Many studies have demonstrated the anticancer activity of polyphyllin VII against various types of cancers, such as colon, liver, and lung cancer, but its effect on breast cancer has not been elucidated. In this study, we demonstrate that polyphyllin VII inhibited proliferation, increased production of intracellular reactive oxygen species, and decreased mitochondrial membrane potential in breast cancer cells. Notably, polyphyllin VII also induced apoptosis via the mitochondrial pathway. Transcriptome sequencing was used to analyze the targets of PPVII in regulating breast cancer cells. Mechanistic studies showed that polyphyllin VII downregulated Son of Sevenless1 (SOS1) and inhibited the MAPK/ERK pathway. Furthermore, PPVII exerted strong antitumor effects in vivo in nude mice injected with breast cancer cells. Our results suggest that PPVII may promote apoptosis through regulating the SOS1/MAPK/ERK pathway, making it a possible candidate target for the treatment of breast cancer.

Keywords:  Breast Cancer; Cell Apoptosis; MAPK/ERK Signaling Pathway; Polyphyllin VII; SOS1

DOI:  https://doi.org/10.1142/S0192415X24500368
Pharmacol Res. 2024 May 06. pii: S1043-6618(24)00149-X. [Epub ahead of print] 107205

Epigenetic Modulations in Triple-Negative Breast Cancer: Therapeutic Implications for Tumor Microenvironment.

Linlin Zhou, Chen-Wei Yu.

  Triple-negative breast cancer (TNBC) is an aggressive subtype lacking estrogen receptors, progesterone receptors and lacks HER2 overexpression. This absence of critical molecular targets poses significant challenges for conventional therapies. Immunotherapy, remarkably immune checkpoint blockade, offers promise for TNBC treatment, but its efficacy remains limited. Epigenetic dysregulation, including altered DNA methylation, histone modifications, and imbalances in regulators such as BET proteins, plays a crucial role in TNBC development and resistance to treatment. Hypermethylation of tumor suppressor gene promoters and the imbalance of histone methyltransferases such as EZH2 and histone deacetylases (HDACs) profoundly influence tumor cell proliferation, survival, and metastasis. In addition, epigenetic alterations critically shape the tumor microenvironment (TME), including immune cell composition, cytokine signaling, and immune checkpoint expression, ultimately contributing to immune evasion. Targeting these epigenetic mechanisms with specific inhibitors such as EZH2 and HDAC inhibitors in combination with immunotherapy represents a compelling strategy to remodel the TME, potentially overcoming immune evasion and enhancing therapeutic outcomes in TNBC. This review aims to comprehensively elucidate the current understanding of epigenetic modulation in TNBC, its influence on the TME, and the potential of combining epigenetic therapies with immunotherapy to overcome the challenges posed by this aggressive breast cancer subtype.

Keywords:  Triple-negative breast cancer; epigenetic modulation and combination; immunotherapy

DOI:  https://doi.org/10.1016/j.phrs.2024.107205
Front Immunol. 2024 ;15 1369892

SOX13 is a novel prognostic biomarker and associates with immune infiltration in breast cancer.

Ting Gao, Baohong Jiang, Yu Zhou, Rongfang He, Liming Xie, Yuehua Li.

  Background: The transcription factor, SOX13 is part of the SOX family. SOX proteins are crucial in the progression of many cancers, and some correlate with carcinogenesis. Nonetheless, the biological and clinical implications of SOX13 in human breast cancer (BC) remain rarely known.Methods: We evaluated the survival and expression data of SOX13 in BC patients via the UNLCAL, GEPIA, TIMER, and Kaplan-Meier plotter databases. Immunohistochemistry (IHC) was used to verify clinical specimens. The gene alteration rates of SOX13 were acquired on the online web cBioportal. With the aid of the TCGA data, the association between SOX13 mRNA expression and copy number alterations (CNA) and methylation was determined. LinkedOmics was used to identify the genes that co-expressed with SOX13 and the regulators. Immune infiltration and tumor microenvironment evaluations were assessed by ImmuCellAI and TIMER2.0 databases. SOX13 correlated drug resistance analysis was performed using the GDSC2 database.
Results: Higher SOX13 expression was discovered in BC tissues in comparison to normal tissues. Moreover, increased gene mutation and amplification of SOX13 were found in BC. Patients with increased SOX13 expression levels showed worse overall survival (OS). Cox analysis showed that SOX13 independently served as a prognostic indicator for poor survival in BC. Further, the expression of SOX13 was also confirmed to be correlated with tumor microenvironment and diverse infiltration of immune cells. In terms of drug sensitivity analysis, we found higher expression level of SOX13 predicts a high IC50 value for most of 198 drugs which predicts drug resistance.
Conclusion: The present findings demonstrated that high expression of SOX13 negatively relates to prognosis and SOX13 plays an important role in cancer immunity. Therefore, SOX13 may potentially be adopted as a biomarker for predicting BC prognosis and infiltration of immune cells.

Keywords:  SOX13; bioinformatics analysis; breast cancer; immunohistochemistry; prognosis

DOI:  https://doi.org/10.3389/fimmu.2024.1369892
Cell Stress Chaperones. 2024 May 02. pii: S1355-8145(24)00072-5. [Epub ahead of print]

Heat shock protein 72 supports extracellular matrix production in metastatic mammary tumors.

Benjamin J Lang, Kristina M Holton, Martin E Guerrero-Gimenez, Yuka Okusha, Patrick T Magahis, Amy Shi, Mary Neguse, Shreya Venkatesh, Anh M Nhu, Jason E Gestwicki, Stuart K Calderwood.

  This study identified tumorigenic processes most dependent on murine HSP72 in the MMTV-PyMT mammary tumor model, which give rise to spontaneous mammary tumors that exhibit HSP72-dependent metastasis to the lung. RNA-seq expression profiling of Hspa1a/Hspa1b (Hsp72) WT and Hsp72-/- primary mammary tumors discovered significantly lower expression of genes encoding components of the extracellular matrix (ECM) in Hsp72 knockout mammary tumors compared to WT controls. In vitro studies found that genetic or chemical inhibition of HSP72 activity in cultured collagen-expressing human or murine cells also reduces mRNA and protein levels of COL1A1 and several other ECM-encoding genes. In search of a possible mechanistic basis for this relationship, we found HSP72 to support the activation of the TGF-β - SMAD3 signaling pathway and evidence of SMAD3 and HSP72 co-precipitation, suggesting potential complex formation. Human COL1A1 mRNA expression was found to have prognostic value for HER2+ breast tumors over other breast cancer subtypes, suggesting a possible human disease context where targeting HSP72 may have a therapeutic rationale. Analysis of human HER2+ breast tumor gene expression data using a gene set comprising ECM- and protein folding-related genes as an input to the statistical learning algorithm, Galgo, found a subset of these genes that can collectively stratify patients by relapse-free survival, further suggesting a potential interplay between the ECM and protein-folding genes may contribute to tumor progression.

Keywords:  COL1A1; Collagen; Extracellular matrix (ECM); HER2; HSP70; Heat shock protein 72 (HSP72)

DOI:  https://doi.org/10.1016/j.cstres.2024.04.006