bims-merabr Biomed News
on Metabolic rewiring in aggressive breast cancer
Issue of 2025–11–16
eight papers selected by
Barbara Mensah Sankofi, University of Oklahoma Health Sciences Center
  1. TIPE3 promotes breast cancer progression and metastasis via the AKT-GSK3β-β-catenin/Snail pathway.
  2. Androgen receptors promote oxidative phosphorylation and resistance to palmitate lipotoxicity in ER-mutant breast cancer.
  3. MTFR1 Promotes Proliferation and Metastasis of Triple-Negative Breast Cancer by Regulating Mitochondrial Metabolism.
  4. RPL17 regulates the progression of breast cancer accompanied by MAPK signaling activation.
  5. GNB2 promotes breast cancer progression by up-regulating HSPA5/GPX4 and inhibiting ferroptosis.
  6. Cancer-Associated Fibroblasts Move and Interact More with Triple-Negative Breast Cancer Cells and Stimulate Their Proliferation in a Hyaluronan-Dependent Manner.
  7. NRG1/PDGFC loop between fibroblasts and cancer cells drives paclitaxel resistance via ferroptosis suppression in breast cancer.
  8. Role of EMT in drug resistance of breast cancer: molecular mechanisms and therapeutic strategies.
  1. Transl Cancer Res. 2025 Oct 31. 14(10): 6667-6680
    TIPE3 promotes breast cancer progression and metastasis via the AKT-GSK3β-β-catenin/Snail pathway.
    Yiling Bai, Jing Wu, Dongmei Yu, Qiang Li, Yan Li, Yufeng Xie.
       Background: The tumor necrosis factor-α-induced protein 8-like 3 (TNFAIP8L3, TIPE3) plays a critical role in phosphoinositide transport and metabolism to facilitate PI3K-AKT signaling activation. Elevated TIPE3 expression has been observed in multiple malignancies, including esophageal, cervical, colon, and lung cancers, suggesting its potential oncogenic role in tumor progression. However, the precise molecular mechanisms by which TIPE3 regulates breast cancer progression remain largely unclear. This study aims to investigate the role of TIPE3 in breast cancer cell growth and metastasis.
    Methods: TIPE3 expression in 100 paired breast cancer and adjacent tissues was analyzed via immunohistochemistry. Quantitative real-time polymerase chain reaction (qRT-PCR) and western blot assessed TIPE3 levels in breast cancer cell lines (MCF7, SKBR3, MDA-MB-231, MDA-MB-468) and normal mammary epithelial cell (MCF10A). TIPE3 overexpression and TIPE3 knockdown lentiviral constructs were generated and transfected into MCF7 and MDA-MB-231 cells. Functional assays, including Cell Counting Kit-8 (CCK-8), colony formation, cell cycle analysis, wound healing, and transwell invasion assays, evaluated proliferation, migration, and invasion. Tumor growth and metastasis were assessed in BALB/c nude mice. Western blot, qRT-PCR, and IHC examined the impact of TIPE3 on AKT-GSK3β-β-catenin/Snail signaling and epithelial-mesenchymal transition (EMT) marker expression.
    Results: TIPE3 expression was significantly upregulated in breast cancer tissues and cell lines. Stable TIPE3 overexpression (MCF7-TIPE3) and TIPE3 knockdown (MDA-MB-231-shTIPE3) cell lines were established. TIPE3 overexpression promoted proliferation, G1/S transition, migration, and invasion, whereas TIPE3 knockdown inhibited these processes and suppressed tumor growth and lung metastasis in nude mice. TIPE3 regulated the AKT-GSK3β-β-catenin/Snail signaling pathway, enhancing EMT marker expression while downregulating E-cadherin.
    Conclusions: TIPE3 expression is elevated in breast cancer and likely promotes breast cancer growth and metastasis through the AKT-GSK3β-β-catenin/Snail pathway. TIPE3 may be a novel therapeutic target for breast cancer.
    Keywords:  AKT-GSK3β-β-catenin/Snail; Breast cancer; growth; metastasis; tumor necrosis factor-alpha-induced protein 8-like 3 (TNFAIP8L3, TIPE3)
    DOI:  https://doi.org/10.21037/tcr-2025-717
  2. Endocrinology. 2025 Nov 11. pii: bqaf168. [Epub ahead of print]
    Androgen receptors promote oxidative phosphorylation and resistance to palmitate lipotoxicity in ER-mutant breast cancer.
    Dane T Sessions, Dillon P Boulton, Nicole S Spoelstra, M Cecilia Caino, Min Yu, Andrew Goodspeed, Jennifer K Richer.
      Aromatase inhibitors (AI) are first-line therapy for postmenopausal women with estrogen receptor-expressing (ER+) breast cancer (BC). AI therapy effectively reduces recurrence and extends lifespan for patients with ER+ breast cancer through long term estrogen deprivation (LTED) resulting from inhibition of the enzyme aromatase that converts androgens to estrogens. However, up to 50% of ER+ BC recurs as AI resistant metastatic disease within 10 years of diagnosis. AI resistant BC upregulates androgen receptors (AR) and mitochondrial oxidative phosphorylation (OXPHOS) and requires OXPHOS and fatty acid oxidation (FAO). The liver and lung, common ER+ BC metastatic sites, have high abundance of the saturated fatty acid palmitate (PA). We asked whether AR signaling regulates OXPHOS in the context of LTED. Using mutant ER-expressing MCF7 and T47D BC cell lines with AR antagonism via the anti-androgen enzalutamide and with shRNA knockdown, we demonstrate that AR supports cell growth, OXPHOS, FAO, and resistance to PA lipotoxicity. We identify AR as a positive regulator of the carnitine acyltransferase family enzyme CRAT that promotes OXPHOS capacity. These studies identify AR as pro-tumor in the LTED setting and as a therapeutic target for ER-mutant BC that develops under the selective pressure of AI therapy.
    Keywords:  androgen receptor; breast cancer; estrogen receptor; fatty acid oxidation; mitochondria; oxidative phosphorylation
    DOI:  https://doi.org/10.1210/endocr/bqaf168
  3. IUBMB Life. 2025 Nov;77(11): e70054
    MTFR1 Promotes Proliferation and Metastasis of Triple-Negative Breast Cancer by Regulating Mitochondrial Metabolism.
    Zhengzhi Zhu, Jing Wang, Jianjun Liu, Guoping Sun.
      Mitochondria, as the center of cellular energy metabolism, play multiple key roles in the progression of triple-negative breast cancer (TNBC). Mitochondrial fission regulator 1 (MTFR1) is a mitochondrial regulatory factor that plays a part in regulating mitochondrial fission and cell development. It is still unknown how MTFR1 functions in TNBC. We discovered MTFR1 to be a crucial gene in TNBC with clinical diagnostic value using database mining analysis. The effects of MTFR1 on TNBC cell proliferation, migration, invasion, and mitochondrial function were determined using the Cell Counting Kit-8, wound healing, and Transwell assays. Nude mouse models were established to explore the impact of MTFR1 on TNBC tumor growth and metastasis. Additionally, western blot and transcriptome sequencing (RNA-seq) were used to investigate the mechanism of MTFR1's involvement in TNBC progression. We used database extraction, WGCNA, Cox regression, and ROC (receiver operating characteristic) curve analysis to identify and confirm MTFR1 as a critical gene in TNBC. In TNBC patients, high MTFR1 expression is related to poor prognosis and diagnostic value. Knockdown of MTFR1 inhibits the proliferation and metastasis of TNBC cells and tumor bodies, affecting mitochondrial function. MTFR1 knockdown inhibits the growth, metastasis, and mitochondrial function of TNBC cells and tumors. Furthermore, transcriptome sequencing and western blot experiments confirmed that MTFR1 knockdown inhibits the activation of the NF-κB signaling pathway. In this study, we report for the first time that MTFR1 is a critical gene upregulated in TNBC. MTFR1 is an oncogene in TNBC and is involved in cell growth, migration, and mitochondrial function, and promotes TNBC progression through the NF-κB signaling pathway. Therefore, targeting MTFR1 may be a promising therapeutic target for TNBC patients.
    Keywords:  MTFR1; NF‐κB signaling pathway; migration; mitochondrial function; proliferation; triple‐negative breast cancer
    DOI:  https://doi.org/10.1002/iub.70054
  4. Med Oncol. 2025 Nov 12. 42(12): 550
    RPL17 regulates the progression of breast cancer accompanied by MAPK signaling activation.
    Yu Cai, Hao Liu, Guobing Yin.
      Breast cancer (BC) is the most frequently diagnosed cancer type and the leading cause of cancer-related mortality among females worldwide. This study aimed to investigate the role of RPL17 in BC. Our findings revealed that the expression of RPL17 in BC tissues and cell lines was significantly elevated compared to normal tissues and cells. The knockout of RPL17 in BC cell lines profoundly inhibited their proliferation, migration, invasion, and cell adhesion abilities. Furthermore, RPL17 knockout (RPL17-KO) cells exhibited increased apoptosis. Mechanistically, RPL17-KO cells demonstrated decreased MAPK signaling. Finally, the overexpression of RPL17 promoted the epithelial-mesenchymal transition (EMT) process in BC cells. RPL17-overexpressing cells displayed enhanced proliferation, migration, invasion, and cell adhesion abilities, alongside reduced apoptosis and increased MAPK signaling. Collectively, this study suggests that RPL17 functions as an important oncogene and may represent a potential therapeutic target for BC.
    Keywords:  BC; MAPK signaling; RPL17; Tumor progression.
    DOI:  https://doi.org/10.1007/s12032-025-03117-1
  5. Mol Cell Biochem. 2025 Nov 15.
    GNB2 promotes breast cancer progression by up-regulating HSPA5/GPX4 and inhibiting ferroptosis.
    Yongxia Wang, Rong Liu, Chenfei Tian, Zhanting Kang, Zhiying Xu, Zihao Wang, Siguang Xu, Jiateng Zhong.
      G protein subunit beta 2 (GNB2) is a potential biomarker identified recently in human cancers. However, the specific role and its underlying mechanism in breast cancer (BRCA) remain unclear. Expression levels of GNB2 were examined in human BRCA tissues and cells by real-time quantitative PCR (qPCR), immunohistochemistry (IHC) and Western blot. Biological functions of GNB2 were determined by a series of in vitro experiments (CCK-8, colony formation assay, Transwell and wound healing) and in vivo ones (subcutaneous transplantation tumor and pulmonary metastasis model). Mechanism of GNB2 in BRCA was explored by co-immunoprecipitation (Co-IP), qPCR, Western blot, flow cytometry and some rescue experiments. Increased expression of GNB2 was found in BRCA, which indicated poorer clinical prognosis of the patients. The over-expression of GNB2 increased proliferation, migration of BRCA cells, while it decreased the intracellular contents of reactive oxygen species (ROS), Fe2+ and malondialdehyde (MDA). In addition, GNB2 over-expression increased the expression of heat-shock-protein family A(HSP70) member 5 (HSPA5) and the expression of glutathione peroxidase 4 (GPX4), which inhibited the cell death induced from Erastin. After knockdown of GNB2, all the above indicators were significantly reversed. Restored expression of HSPA5 in BRCA cells with GNB2 knockdown rescued the effects. Therefore, the current study verifies GNB2 as an important driver in BRCA progression by up-regulating HSPA5/GPX4 and inhibiting ferroptosis, which highlights its potential role in the clinical diagnosis and treatment of BRCA.
    Keywords:  Breast cancer; Ferroptosis; GNB2; HSPA5; Progression
    DOI:  https://doi.org/10.1007/s11010-025-05406-9
  6. Cells. 2025 Oct 23. pii: 1663. [Epub ahead of print]14(21):
    Cancer-Associated Fibroblasts Move and Interact More with Triple-Negative Breast Cancer Cells and Stimulate Their Proliferation in a Hyaluronan-Dependent Manner.
    Sz-Ying Hou, Sarah C Macfarlane, Ariadna Gómez Torijano, Hyejeong Rosemary Kim, Marieke Rosier, Katalin Dobra, Penelope D Ottewell, Annica K B Gad.
      While normal fibroblasts suppress tumor growth, during cancer initiation and progression, this capacity can be lost and even switched to tumor-promoting, for reasons that are not understood. In this study, we aimed to determine differences between patient-derived cancer-associated fibroblasts and fibroblasts from healthy breast tissue to identify if and how these changes stimulate Triple-negative breast cancer (TNBC). Two-dimensional and three-dimensional mono and co-cultures of TNBC cells with fibroblasts from healthy breast or TNBC were analyzed for cell contractility, migration, distribution, proliferation, and hyaluronan production by traction force microscopy, live cell imaging, flow cytometry, Western blot, and ELISA. In 3D spheroid co-culture, CAFs migrated into the tumor mass, mixing with tumor cells, whereas normal fibroblasts remained separate. In 2D, CAFs showed increased cell migration and contractile force, and, in both 2D and 3D co-culture, CAFs increased the proliferation of TNBC cells. CAFs showed increased production of hyaluronan, as compared to normal fibroblasts, and loss of hyaluronan synthase 2 reduced CAF-induced stimulation of TNBC proliferation. These findings suggest that increased production of hyaluronan by TNBC CAFs enhances their capacity to mix with and induce the proliferation of cancer cells, and that the production of hyaluronan by CAFs can be a future therapeutic target against TNBC.
    Keywords:  3D spheroid co-culture models; cancer-associated fibroblasts; hyaluronan; triple-negative breast cancer
    DOI:  https://doi.org/10.3390/cells14211663
  7. Cell Death Discov. 2025 Nov 10. 11(1): 520
    NRG1/PDGFC loop between fibroblasts and cancer cells drives paclitaxel resistance via ferroptosis suppression in breast cancer.
    Wan-Li Duan, Xue-Jie Wang, Li-Hui Gu, Ai Guo, Yi-Yue Ding, Ping Lin, Bao-Gang Zhang.
      Breast cancer (BC) is one of the leading diseases that severely threaten women's lives and health worldwide, with chemoresistance remaining a major challenge in its treatment. The tumor microenvironment, particularly cancer-associated fibroblasts (CAFs), plays a critical role in the chemoresistance of tumor cells, but the underlying mechanisms involved still require further exploration. This study aims to investigate the role and potential mechanisms of the positive feedback loop formed by CAF-derived NRG1 and BC cell-derived PDGFC in paclitaxel resistance. To this end, we isolated primary CAFs from BC patients and established co-culture systems with BC cell lines to observe the impact of CAFs on paclitaxel resistance in BC cells. Exogenous NRG1 and the knockdown of NRG1 in CAFs were used to reveal the regulatory role of CAF-derived NRG1 in paclitaxel resistance in BC cells. CCK-8 assay, transmission electron microscopy, MDA and GSH/GSSG content measurements, as well as JC-1 assay, were used to assess ferroptosis levels in BC cells. Additionally, exogenous PDGFC and co-culture systems were used to investigate the effects of tumor cell-derived PDGFC on fibroblasts. Using a BC ectopic xenograft mouse model, we investigated the regulatory role of NRG1 and PDGFC in paclitaxel resistance in vivo. Our results showed that CAF-derived NRG1 significantly promoted paclitaxel resistance and ferroptosis escape in BC cells, while the AKT inhibitor effectively suppressed this effect. Moreover, BC cell-derived PDGFC activated fibroblasts and induced their high expression of NRG1. These findings suggest that CAF-derived NRG1 enhances ferroptosis escape and paclitaxel resistance in BC cells through the AKT/mTOR pathway, while also inducing cancer cells to express high levels of PDGFC. In turn, cancer cell-derived PDGFC promotes fibroblast activation and high NRG1 expression, forming a positive feedback loop between NRG1 and PDGFC. This feedback loop ultimately results in a malignant cycle of paclitaxel resistance in BC.
    DOI:  https://doi.org/10.1038/s41420-025-02785-2
  8. Front Oncol. 2025 ;15 1680751
    Role of EMT in drug resistance of breast cancer: molecular mechanisms and therapeutic strategies.
    Yifan Luo, Renwang Sheng, Xin Tan, Jun Gu.
      Breast cancer, as the most common cancer in women, is a highly heterogeneous and complex tumor. One of the important reasons for the poor prognosis and high mortality of breast cancer patients is drug resistance. More and more evidence shows that epithelial-to-mesenchymal transition (EMT) is a key driver of malignant behavior of breast cancer, and also the core promoter of drug resistance. Multiple EMT-related signaling pathways activate EMT-transcription factors (EMT-TFs) and interact with each other, ultimately inducing drug resistance. The role of EMT in promoting invasion and metastasis has been studied in detail and systematically summarized, but its role in drug resistance of breast cancer has not been elucidated comprehensively. The purpose of this review is to clarify the EMT-related regulatory network in breast cancer and the possible mechanisms of EMT-induced drug resistance. Moreover, we have discussed the potential therapeutic advantages of reversing EMT and drug resistance by effectively targeting key elements of the regulatory network, with particular emphasis on EMT-related signaling pathways and microRNAs. This review summarizes the drug resistance of breast cancer induced by EMT systematically, which is of great significance for solving the drug resistance problem of breast cancer and improving the prognosis of patients.
    Keywords:  EMT; breast cancer; cancer stem cells; drug resistance; microRNA
    DOI:  https://doi.org/10.3389/fonc.2025.1680751
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