bims-merabr 2025-05-04 papers

bims-merabr

Biomed News

on Metabolic rewiring in aggressive breast cancer

Issue of 2025–05–04
ten papers selected by
Barbara Mensah Sankofi, University of Oklahoma Health Sciences Center

The SGK3/GSK3β/β-catenin signaling promotes breast cancer stemness and confers resistance to alpelisib therapy.
EMC2 promotes breast cancer progression and enhances sensitivity to PDK1/AKT inhibition by deubiquitinating ENO1.
MicroRNA-593-3p Inhibits Growth and Metastasis of Human Breast Cancer Cells by Regulating TIMM17A Expression.
LINC00534 promotes breast cancer progression by targeting the miR-139-5p/HMGB2 axis.
Leucine rich repeat containing 15 promotes triple-negative breast cancer proliferation and invasion via the ITGB1/FAK/PI3K signalling pathway.
GRB2 promotes brain metastasis in HER2-positive breast cancer by regulating the Ras/MAPK pathway.
Targeting Glycolysis for Treatment of Breast Cancer Resistance: Current Progress and Future Prospects.
Runx1 activates the transformation of adipocytes into cancer-associated adipocytes by downregulating Plin1.
Macrophage Polarization-Based Analysis of the Role of the FOXM1/KIF20A Axis in Breast Cancer Metastasis.
Comparative Glycoproteomic Analysis of Mouse 4T1 Breast Cancer Model.

Int J Biol Sci. 2025 ;21(6): 2462-2475

The SGK3/GSK3β/β-catenin signaling promotes breast cancer stemness and confers resistance to alpelisib therapy.

Tingting Kang, Yuanfang Wang, Yaxin Jiang, Shunjie Chen, Na Lin, Minyan Guo, Haotu Zhu, Di Tang, Xiaofan Ding, Mian He.

  Drug resistance is the leading cause of death in patients with advanced tumors. Alpelisib, a selective PIK3CA inhibitor, has been recently approved for treating advanced breast cancer. However, drug resistance is inevitable, and the mechanisms behind alpelisib-associated resistance remain elusive. To address this problem, we established an alpelisib-resistant breast cancer cell model and confirmed that the resistant cells exhibited enhanced abilities in colony formation, migration, anti-apoptosis, spheroidization, tumor formation and metastasis. Further analysis revealed that SGK3 was significantly upregulated in alpelisib-resistant cells, which was strongly associated with tumor stemness. Additionally, we observed that SGK3 promoted tumor cell stemness by activating GSK3β/β-catenin signaling pathway, leading to the resistance to alpelisib in breast cancer. Finally, we demonstrated that SGK3 inhibitor could restore the sensitivity of resistant cells to alpelisib. Collectively, these findings suggest that SGK3 could be a novel therapeutic target for breast cancer patients who developed resistance to alpelisib.

Keywords:  Alpelisib; SGK3; drug resistance; stem cell; β-catenin

DOI:  https://doi.org/10.7150/ijbs.104850
Int J Biol Sci. 2025 ;21(6): 2629-2646

EMC2 promotes breast cancer progression and enhances sensitivity to PDK1/AKT inhibition by deubiquitinating ENO1.

Shihan Xiao, Shangxuan Jiang, Chengxu Wen, Han Wang, Wenxiang Nie, Jianguo Zhao, Bo Zhang.

  Breast cancer is the most common malignant tumor worldwide, causing 685,000 deaths in 2020, and this number continues to rise. Identifying the molecular mechanisms driving breast cancer progression and potential therapeutic targets are currently urgent issues. Our previous work and bioinformatics analysis shows that the expression of Endoplasmic Reticulum Membrane Protein Complex Subunit 2 (EMC2) is up-regulated in breast cancer and is correlated with shortened overall survival of patients. However, the mechanism of EMC2 in breast cancer is yet to be elucidated. In this study, we identified that EMC2 promotes breast cancer proliferation and metastasis by activating the PDK1/AKT (T308)/mTOR (S2448) signaling pathway and can serve as a candidate target for PDK1/AKT inhibition. Mechanistically, EMC2 serves as a "scaffold" protein to recruit the deubiquitinating enzyme (DUB) USP7 for ENO1 deubiquitylation to stabilize its expression, thereby initiating downstream B-MYB/PDK1/AKT (T308)/mTOR (S2448) signal cascade. Silencing EMC2 significantly weaken the proliferation/metastasis potential of breast cancer in vitro and in vivo, but made tumor cell sensitive to PDK1/AKT inhibition. Overexpression of EMC2 leads to exactly the opposite result. This study reveals the EMC2/USP7/ENO1/B-MYB protumorigenic axis in breast cancer and identifies EMC2 as a candidate target for PDK1/AKT inhibitory therapy.

Keywords:  Breast cancer; Deubiquitination; Drug sensitivity; EMC2; ENO1; PDK1; Scaffold

DOI:  https://doi.org/10.7150/ijbs.109192
Biochem Genet. 2025 Apr 30.

MicroRNA-593-3p Inhibits Growth and Metastasis of Human Breast Cancer Cells by Regulating TIMM17A Expression.

Zhigang Yang, Jun Zhang, Liguo Yang, Chenzeyue Qian, Lina Jin.

  Breast cancer poses significant therapeutic challenges, necessitating the identification of novel molecular targets for effective treatment. This study explores the tumor-suppressive role of miR-593-3p and its regulatory interaction with TIMM17A in breast cancer. Expression analysis revealed a marked downregulation of miR-593-3p in breast cancer cell lines compared to normal mammary epithelial cells. Functional assays demonstrated that miR-593-3p overexpression in MDA-MB-231 cells inhibited proliferation, suppressed colony formation, and induced apoptosis, as confirmed by CCK-8 and Annexin V/PI assays. Bioinformatics predictions and dual luciferase reporter assays identified TIMM17A as a direct target of miR-593-3p. Western blot analysis showed that miR-593-3p overexpression considerably reduced TIMM17A levels. Furthermore, TIMM17A was upregulated in breast cancer tissues and correlated with poor clinical outcomes. Knockdown of TIMM17A suppressed cell growth and invasion, while its overexpression counteracted the inhibitory effects of miR-593-3p. Transwell assays further demonstrated that miR-593-3p reduced the invasive potential of MDA-MB-231 cells by regulating TIMM17A These findings indicate that miR-593-3p functions as a tumor suppressor by targeting TIMM17A, influencing both proliferative and invasive properties of breast cancer cells. The identification of this regulatory axis suggests that miR-593-3p could serve as a promising therapeutic target for breast cancer treatment.

Keywords:  Breast cancer; Expression; MiR-593-3p; MicroRNA; TIMM17A

DOI:  https://doi.org/10.1007/s10528-025-11109-z
Discov Oncol. 2025 May 02. 16(1): 655

LINC00534 promotes breast cancer progression by targeting the miR-139-5p/HMGB2 axis.

Qiaomei Liu, Wei Xiong.

   BACKGROUND: Breast cancer is the most prevalent malignancy among women, it is crucial to identify sensitive biomarkers for prognosis and treatment of breast cancer patients. Emerging research has demonstrated the involvement of long noncoding RNAs (lncRNAs) in the advancement of breast cancer. LINC00534 has recently emerged as a potential regulator in multiple malignancies, yet its clinical significance and molecular mechanisms in breast cancer remain poorly characterized.
OBJECTIVE: The purpose of this study was to explore the function of LINC00534 and miR-139-5p in breast cancer progression, as well as the mechanisms that underpin its actions.
METHODS: Tumor and normal tissues were collected from 80 breast cancer patients. qRT-PCR was performed to detect LINC00534 expression in tissues. Kaplan-Meier analysis was used to assess survival differences between groups and the correlation between LINC00534 expression and clinical outcomes. CCK-8 assay was used to evaluate cell proliferation to assess LINC00534's effect on tumor growth. To evaluate the impact of LINC00534 on tumor metastasis, transwell assay was used to detect the migration and invasion abilities of cells. Moreover, dual-luciferase assay was used to verify the relationship within the LINC00534/miR-139-5p/HMGB2 axis.
RESULT: LINC00534 was significantly upregulated in breast cancer tumor tissues and cell lines (p < 0.001). Higher LINC00534 expression correlated with poorer prognosis in breast cancer patients, including shorter survival and higher recurrence risk (Log-rank p = 0.014). Furthermore, LINC00534 promoted breast cancer cell proliferation, migration, and invasion (all p < 0.001) via its interaction with the miR-139-5p/HMGB2 axis.
CONCLUSION: LINC00534 may serve as a prognostic marker and the LINC00534/miR-139-5p/HMGB2 axis could be a therapeutic target for breast cancer.

Keywords:  Breast cancer; LINC00534; Prognosis; miR-139-5p

DOI:  https://doi.org/10.1007/s12672-025-02483-6
Sci Rep. 2025 Apr 25. 15(1): 14535

Leucine rich repeat containing 15 promotes triple-negative breast cancer proliferation and invasion via the ITGB1/FAK/PI3K signalling pathway.

Xiao Wu, Yameng Liu, Yinxi Hu, Fang Su, Zishu Wang, Yongxia Chen, Zhixiang Zhuang.

  Leucine rich repeat containing 15 (LRRC15) is recognized for its intimate association with the extracellular matrix, where it modulates fibroblast function and shapes the immune landscape within the tumour microenvironment. The specific expression patterns and molecular contributions of LRRC15 in triple-negative breast cancer(TNBC) have not been fully elucidated. This study aimed to delineate the clinical relevance and biological implications of LRRC15 in TNBC, and to assess its potential as a novel therapeutic target for this disease. Our findings revealed robust overexpression of LRRC15 in TNBC tumour tissues and cell lines, which was inversely correlated with patient survival outcomes. Notably, the suppression of LRRC15 expression led to pronounced inhibition of TNBC cell proliferation, invasion, and migration both in vitro and in vivo. Mechanistically, we established that LRRC15 interacts with Integrin Beta 1(ITGB1), facilitating the phosphorylation of the T788/T789 residues on ITGB1 and recruiting focal adhesion kinase (FAK) to the site of integrin aggregation. This recruitment promotes the downstream phosphorylation of PI3K and AKT, suggesting that LRRC15 is a key activator of the ITGB1/FAK/PI3K signalling pathway. Collectively, our data indicate that LRRC15 is a critical promoter of TNBC cell proliferation and metastasis through the activation of this signalling pathway, identifying LRRC15 as a promising candidate for therapeutic intervention in TNBC.

Keywords:  ITGB1/FAK/PI3K signalling pathway; Invasion; LRRC15; Proliferation; TNBC

DOI:  https://doi.org/10.1038/s41598-025-98661-1
Sci Rep. 2025 Apr 27. 15(1): 14736

GRB2 promotes brain metastasis in HER2-positive breast cancer by regulating the Ras/MAPK pathway.

Hongyu Li, Yalin Zhang, Xiao Han, Bingyu Li, Dan Liu, Gang Sun.

  Brain metastasis is emerging as the most serious concern for breast cancer patients. HER2-positive breast cancer is more prone to undergo brain metastasis than other subtypes; notably, there has been little improvement in the treatment of brain metastasis .Our study confirmed the relevance of HER2 status to brain metastasis risk via clinical data analysis and revealed that exerts GRB2 tumorigenic effects by regulating the Ras/MAPK pathway in vivo and in vitro. Both an in situ injection model and a direct cerebral injection model were used to explore the ability of GRB2 to promote the brain metastasis. Results indicated that HER2- positive is a risk factor for brain metastasis according to clinical data. GRB2 enhances proliferation, migration, and invasion while suppressing apoptosis in HER2-positive breast cancer cells in vitro, primarily by regulating phosphorylation and alternative splicing of key proteins within the Ras/MAPK pathway. Notably, tumor cells were able to cross the blood‒brain barrier in both models assessed in this study. Thus, GRB2 is an oncogenic factor that contributes to the malignancy of HER2-positive breast cancer, GRB2 and HER2 can synergistically promote tumor cell penetration of the blood‒brain barrier and induce metastasis.

Keywords:  Brain metastasis; GRB2; HER2-positive breast cancer; Ras/MAPK pathway

DOI:  https://doi.org/10.1038/s41598-025-99685-3
Int J Biol Sci. 2025 ;21(6): 2589-2605

Targeting Glycolysis for Treatment of Breast Cancer Resistance: Current Progress and Future Prospects.

Zixu Niu, Jing He, Siyuan Wang, Bingjian Xue, Hao Zhang, Ruohan Hou, Zimeng Xu, Jing Sun, Fucheng He, Xinhong Pei.

  Breast cancer stands as one of the most prevalent malignant tumors threatening women's health and is a leading cause of cancer-related mortality. Its treatment faces significant challenges, including drug tolerance and disease recurrence. Glycolysis serves not only as a critical metabolic pathway for energy acquisition in breast cancer cells but also essentially promotes tumor proliferation, invasion, metastasis, and the development of resistance to therapy. Recent studies have revealed a close association between glycolytic reprogramming and drug resistance in breast cancer, with high-level glycolysis emerging as a hallmark of malignancy, deeply involved in the initiation and progression of tumors. This review summarizes recent advances in research on key enzymes and signaling pathways regulating glycolysis within the bodies of breast cancer patients. It explores in depth these molecular mechanisms and their complex interaction networks, offering a fresh perspective on overcoming drug resistance in breast cancer. Moreover, it underscores the importance of developing specific inhibitors targeting key enzymes and regulators of glycolysis and suggests that combining such inhibitors with existing anticancer drugs could substantially enhance therapeutic outcomes for breast cancer patients and reduce the occurrence of drug resistance.

Keywords:  Breast cancer; Drug resistance; Glycolysis; Glycolytic inhibitors; Targeted therapy; Tumor metabolism

DOI:  https://doi.org/10.7150/ijbs.109803
Exp Cell Res. 2025 Apr 23. pii: S0014-4827(25)00169-7. [Epub ahead of print]448(2): 114573

Runx1 activates the transformation of adipocytes into cancer-associated adipocytes by downregulating Plin1.

Boning Guo, Kai Wang, Jing Wu, Huimin Yu, Chong Geng, Yi Jin, Yongfeng Song.

  Adipocytes play a pivotal role in the breast tumor microenvironment, with the capacity to differentiate into cancer-associated adipocytes (CAAs) under the influence of breast cancer cells. This transformation significantly contributes to the formation and progression of breast cancer; however, the mechanisms underlying this interaction remain poorly understood. This study aims to illuminate these interactions by establishing an in vitro co-culture system of mature adipocytes and breast cancer cells. RNA sequencing analysis identified elevated runt-related transcription factor 1 (Runx1) expression in CAAs. Furthermore, Runx1 expression was also increased in the peritumoral adipose tissue of both breast cancer mouse models and clinical patient samples. Overexpression of Runx1 in 3T3-L1 preadipocytes resulted in reduced adipocyte volume, decreased lipid droplet size, diminished expression of mature adipocyte markers, and an increase in pro-inflammatory factor levels. These findings suggest that Runx1 overexpression facilitates the transformation of adipocytes into CAAs, thereby enhancing breast cancer cell migration and invasion. Conversely, Runx1 knockdown in CAAs diminished their supportive role in cancer progression. Mechanically, Runx1 enhances breast cancer development by regulating perilipin 1 (Plin1) levels, the overexpression of Plin1 in adipocytes inhibited the effect of Runx1 to promote the transition of adipocytes into CAAs. Our findings propose that targeting Runx1 in CAAs may represent a novel therapeutic strategy for breast cancer intervention.

Keywords:  Breast cancer; Cancer-associated adipocytes; Invasion; Migration; Runx1

DOI:  https://doi.org/10.1016/j.yexcr.2025.114573
Cell Biochem Biophys. 2025 Apr 28.

Macrophage Polarization-Based Analysis of the Role of the FOXM1/KIF20A Axis in Breast Cancer Metastasis.

Yuanbin Wang, Ruimin Ma, Qing Yang, Lijun Yang, Xiangli Li, Zhihao Wu.

  To investigate the potential molecular processes underlying the function of forkhead box M1 (FOXM1)-mediated macrophage polarization in breast cancer (BC). The expression levels of Kinesin family member 20 A (KIF20A) and FOXM1 in BC tissues and tumor-associated macrophages (TAMs) were determined using RT-qPCR. Following co-culture of macrophages with BC cells, the impact of FOXM1 on the proliferation, invasive migration ability, and epithelial-mesenchymal transition (EMT) of BC cells was assessed using cell counting kit-8, Transwell, and Western blot assays respectively. Both the chromatin immunoprecipitation (ChIP) test and the dual luciferase reporter gene assay were used to confirm the connection between FOXM1 and KIF20A. Furthermore, the effect of FOXM1 on BC cell growth in vivo was evaluated via subcutaneous tumor formation assay conducted in nude mice. BC cell growth and metastasis were aided by M2 macrophage polarization. KIF20A and FOXM1 expression levels were markedly elevated in both TAMs and BC tissues. FOXM1 drived M2 polarization of macrophages by transcriptionally activating KIF20A. In vitro studies have demonstrated that FOXM1, through its regulation of KIF20A, enhanced BC cell proliferation, migration, invasion, and EMT. The upregulation of KIF20A expression by FOXM1 promotes M2 polarization of macrophages, thereby facilitating BC cell proliferation and metastasis.

Keywords:  Breast cancer; FOXM1; KIF20A; Macrophage; Metastasis

DOI:  https://doi.org/10.1007/s12013-025-01755-w
Curr Med Chem. 2025 Apr 29.

Comparative Glycoproteomic Analysis of Mouse 4T1 Breast Cancer Model.

Aik-Aun Tan, Yin-Ling Wong, Subash C B Gopinath, Lik Voon Kiew, Sreenivasan Sasidharan, Yeng Chen.

   BACKGROUND: Glycosylation is a post-translational modification process that plays a fundamental role in malignant transformation. Moreover, aberrant glycosylation is known to be associated with cancer progression. Thus, the characterization of cancer-specific protein glycosylation profiles might reveal important diagnostic and/or prognostic biomarkers for cancer.
OBJECTIVE: In the present study, we have analysed serum protein and glycoprotein profiles during breast cancer progression using a mouse model. Specifically, 4T1 tumour cells were injected into the mammary fat pad of BALB/c mice to induce tumours.
METHODS: Sera samples were subsequently collected weekly for four weeks and examined using two-dimensional electrophoresis (2D-E) coupled with lectin-based analysis, followed by mass spectrometry.
RESULTS: This glycoproteomic profiling identified eight differentially expressed proteins, of which alpha-1 protease inhibitor 2, contraption (CON), haptoglobin (HP), and kininogen-1 were significantly up-regulated during the first 4 weeks of tumour progression. Notably, aberrantly N-glycosylated prothrombin was also detected in sera samples from all mice over the 4 weeks post-tumour injection. Additionally, O-glycosylated alpha-2-macroglobulin, CON, and HP were detected in weeks 1 and 2, whereas O-glycosylated alpha-2-HS-glycoprotein and CON were detected on weeks 3 and 4 post-implantation.
CONCLUSION: Our findings indicate that the combination of 2D-E with lectin-based chromatography represents an effective approach for identifying prognostic biomarkers for breast cancer.

Keywords:  4T1 model; Breast cancer; glycoproteomic; glycosylation; lectin.

DOI:  https://doi.org/10.2174/0109298673360978250329065548