bims-merabr Biomed News
on Metabolic rewiring in aggressive breast cancer
Issue of 2026–07–12
eleven papers selected by
Barbara Mensah Sankofi, University of Oklahoma Health Sciences Center
  1. The deubiquitinase USP25 contributes to stemness and malignant progression of breast cancer by stabilizing C1ql4.
  2. Obesity and Age Elevate Tissue-Resident Microbiota Akkermansia muciniphila to Induce Oxidative Stress and Promote Breast Cancer Risk.
  3. Beyond the scaffold: extracellular matrix uptake in breast cancer.
  4. Mechano-activation of Osteocytic Connexin Hemichannels Prime Microenvironment in Suppressing Breast Cancer Bone Metastasis.
  5. LMAN2 promotes breast cancer progression and deduces cell sensitivity to doxorubicin through stearoyl-CoA desaturase.
  6. Loss of ETV4 triggers PPM1E downregulation and AMPK-ULK1-dependent autophagy to promote intrinsic trametinib resistance in breast cancer.
  7. Targeting Lipid Metabolism Enzymes in Breast Cancer: Mechanistic Basis and Therapeutic Vulnerabilities.
  8. Transcription Factors in Breast Cancer Oncogenesis and Progression.
  9. Cancer-associated adipocytes promote breast cancer progression by upregulating miR-106b-3p to target SLK.
  10. Distinct metabolic dependency on BCAA defines cancer stemness and malignancy in human triple-negative breast cancer.
  11. mRNA and protein expression of fetal insulin receptor in breast cancer cell lines and tissues.
  1. Sci Rep. 2026 Jul 07. pii: 20880. [Epub ahead of print]16(1):
    The deubiquitinase USP25 contributes to stemness and malignant progression of breast cancer by stabilizing C1ql4.
    Xiao Li, Zhijun Xing, Haotian Fang, Mingzhen Zhao, Qingxia Li, Na Feng, Fan Xu.
      Breast cancer (BC) remains one of the most aggressive and life-threatening types of female cancer. Cancer stem cells (CSCs) are closely correlated with the progression and metastasis of cancers. This study aimed to explore the role of ubiquitin-specific peptidase 25 (USP25) in breast cancer metastasis and stemness. Cell counting kit 8 (CCK-8) and 5-ethynyl-2'-deoxyuridine (EDU) assay were performed to measure cell viability and proliferation. Xenograft tumor model was established to determine in vivo growth of cancer cells. Flow cytometry was used to measure cell apoptosis. Western blot and qPCR were performed to assess the expression of apoptosis and cancer stemness biomarkers. Cancer cell self-renewal ability was analyzed by the sphere formation assay. Clinical samples were collected to measure the expression of USP25 and C1ql4 (C1q-like 4). Knockdown of USP25 suppressed the in vitro and in vivo growth of breast cancer cells and increased cell apoptosis, inhibited the self-renewal ability, downregulated the expression of cancer stemness biomarkers, and reduced the stability of C1ql4 protein, whereas overexpression of C1ql4 could reverse these effects. The clinical analysis demonstrated that USP25 and C1ql4 were highly expressed in breast cancer tissues and presented a positive correlation. Our data indicated that knockdown of USP25 suppressed the stemness growth of breast cancer cells via reducing the stability of C1ql4 protein. These findings provide USP25/C1ql4 as a potential therapeutic target for breast cancer.
    Keywords:  C1ql4; Cancer stem cells; USP25; Ubiquitination
    DOI:  https://doi.org/10.1038/s41598-026-49272-x
  2. Cancer Res. 2026 Jul 09.
    Obesity and Age Elevate Tissue-Resident Microbiota Akkermansia muciniphila to Induce Oxidative Stress and Promote Breast Cancer Risk.
    Kenysha Yj Clear, Alana A Arnone, Yu-Ting Tsai, Adam S Wilson, Maria L Carneiro Buchele, Cristina M Furdui, Marissa Howard-McNatt, Akiko Chiba, David R Soto-Pantoja, Janet A Tooze, Abigail Peoples, Mary L Duet, Adam Katz, Dilip D Giri, Neil M Iyengar, Katherine L Cook.
      Obesity is a modifiable risk factor for postmenopausal breast cancer. As obesity-gut microbiome interactions are well known, obesity might also impact tissue-resident microbiome populations as a mechanism promoting breast cancer. Using non-cancerous breast tissue samples, we demonstrated that obesity and aging interact to shift the tissue-resident microbiome in breast cancer patients. Breast tissue from postmenopausal women with obesity displayed a significantly different α-diversity and β-diversity than pre- and postmenopausal women without obesity. At the species level, breast tissue from postmenopausal women with obesity expressed elevated Akkermansia muciniphila abundance when compared with all other groups. A secondary cohort of non-cancerous breast tissue from reduction mammoplasty patients indicated participant body mass index correlates with breast A. muciniphila abundance. Elevated mammary gland A. muciniphila in female MMTV-PyMT mice fed a high-fat Western diet increased tumorigenesis, tumor multiplicity, and oxidative stress markers, and administration of antioxidant N-acetylcysteine reduced A. muciniphila-induced tumorigenesis and redox perturbations. In an orthotopic progression model, mammary gland A. muciniphila in Western diet-fed mice promoted ER+ tumor growth and lung metastases. Taken together, these results suggest obesity and aging interact to enrich breast A. muciniphila abundance, modifying tissue redox balance as a risk factor for obesity-mediated postmenopausal breast cancer.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-2087
  3. Biochem Soc Trans. 2026 Jul 29. 54(7): 915-922
    Beyond the scaffold: extracellular matrix uptake in breast cancer.
    Elena Rainero.
      Breast cancer is associated with a highly fibrotic tumour microenvironment, where cancer-associated fibroblasts (CAFs) secrete excessive amounts of extracellular matrix (ECM). Fibrosis and collagen deposition correlate with poor patient survival, indicating that the ECM plays a role in promoting tumorigenesis. The ECM is constantly remodelled through extracellular and intracellular degradation pathways. While protease-dependent extracellular ECM degradation has been well studied, the intracellular degradation pathway is less understood. Here, I will describe the evidence supporting a role for ECM internalisation and lysosomal degradation in promoting breast cancer progression. Both cancer cells and CAFs are reported to uptake ECM components via different ECM receptors. These include TEM8 in fibroblasts, Endo180 in both cancer cells and CAFs, and α2β1 integrin in cancer cells. Importantly, this process has been associated with metabolic reprogramming under nutrient deprivation conditions representative of the breast cancer TME, cancer cell growth in vitro and in vivo, and cancer cell migration and invasion. Therefore, regulators of ECM endocytosis and lysosomal delivery might represent novel potential targets to prevent tumour growth and metastasis in ECM-rich breast cancers.
    Keywords:  breast cancers; cancer cell metabolism; cancer-associated fibroblasts; extracellular matrix; tumour microenvironment
    DOI:  https://doi.org/10.1042/BST20250121
  4. Cancer Lett. 2026 Jul 09. pii: S0304-3835(26)00486-6. [Epub ahead of print] 218722
    Mechano-activation of Osteocytic Connexin Hemichannels Prime Microenvironment in Suppressing Breast Cancer Bone Metastasis.
    Xuewei Wang, Rui Hua, Manuel A Riquelme, Jingruo Zhang, Lidan Zhang, Sumin Gu, Lu-Zhe Sun, Francisca M Acosta, Jean X Jiang.
      Mechanical stress profoundly influences tumor-bone interaction. However, the underlying mechanism is largely elusive. Here, we reveal that mechanical loading activates osteocyte connexin 43 (Cx43) hemichannels (HCs) and promotes the release of soluble factors, thus establishing a tumor-suppressive bone microenvironment that limits the growth of metastatic breast cancer in bone. Conditioned media from fluid flow shear stress (FFSS)-stimulated osteocyte MLO-Y4 cells significantly inhibited tumor spheroid expansion and migration of both triple-negative and ER-positive breast cancer cells. This inhibitory effect was abolished by blockade of Cx43 HCs. FFSS-activated osteocytes also reduced filopodial extensions and epithelial-mesenchymal transition (EMT) marker expression in cancer cells. Mechanistically, FFSS stimulation induced Cx43 HC-mediated release of prostaglandin E2 (PGE2) and ATP, which exerted opposing effects: PGE2 promoted, while ATP suppressed, breast cancer cells. The relative ATP:PGE2 ratio served as a key determinant of the extent of tumor inhibition. In vivo tibial loading for two weeks prior to tumor inoculation further demonstrated the anti-metastatic function of Cx43 HCs. Mechanical loading suppressed breast cancer proliferation, growth, and osteolytic damage in wild-type (WT) and R76W transgenic mice (defective in gap junctions (GJs) but retaining HCs), but not in Δ130-136 mice (defective in both HCs and GJs). Consistently, Cx43(M1)-mediated HC blockade attenuated the tumor-suppressive effects of mechanical loading. ATP and PGE2 levels were elevated in loaded tibiae of WT and R76W, but not Δ130-136 mice. Collectively, these findings identify Cx43 HC activation by mechanical stress as a key mechanism driving the bone's transition from a metastasis-permissive to a metastasis-resistant microenvironment, mediated by ATP-dominant paracrine signaling from osteocytes that suppresses breast cancer progression.
    Keywords:  Connexin hemichannel; bone microenvironment; breast cancer bone metastasis; mechanical loading
    DOI:  https://doi.org/10.1016/j.canlet.2026.218722
  5. Breast Cancer Res. 2026 Jul 08.
    LMAN2 promotes breast cancer progression and deduces cell sensitivity to doxorubicin through stearoyl-CoA desaturase.
    Changjiao Yan, Fengqiang Cui, Chutuo Liu, Rui Ling, Meiling Huang, Ting Wang.
       BACKGROUND: Dysregulated lipid metabolism and chemoresistance are key drivers of breast cancer progression. Lectin, mannose-binding 2 (LMAN2) is frequently overexpressed in human breast tumors and functions as an oncogenic driver. However, whether LMAN2 contributes to chemoresistance remains unknown.
    METHODS: We integrated multi-omics data from 1,085 primary tumors and matched normal tissues (from GEPIA and UALCAN) with functional studies in breast cancer cell lines and a doxorubicin (ADM)-treated nude mouse xenograft model. LMAN2 expression was modulated via siRNA/shRNA-mediated silencing or lentivirus-driven overexpression. Cellular phenotypes-including proliferation, migration, apoptosis, and response to ADM were systematically assessed. RNA-sequencing, untargeted lipidomics, and rescue experiments identified stearoyl-CoA desaturase (SCD) as a critical downstream effector. IC50 shifts and epistasis analysis further validated the role of the LMAN2/SCD axis in chemoresistance.
    RESULTS: LMAN2 mRNA was elevated across all molecular subtypes (luminal > HER2 > triple-negative) and predicted poorer overall survival (P = 5 × 10-4) and progression-free survival (P = 0.018). Silencing LMAN2 reduced clonogenicity by ~ 45% and migration by 37-63%, whereas overexpression increased cell viability by 1.4-1.7-fold and doubled motility. Knockdown of LMAN2 decreased the ADM IC50 by 4-5 fold, abolished macroscopic colony formation, and elevated apoptosis rates from 15 to 18% to 39-41%; these effects were reversed upon LMAN2 overexpression. In vivo, shLMAN2 combined with ADM reduced tumor volume and weight by 72% and 75%, respectively, compared to ADM alone (P < 0.001). Mechanistically, LMAN2 loss downregulated genes involved in "cholesterol homeostasis" and reduced total cellular cholesterol by 24%. SCD emerged as the most significantly downregulated enzyme and fully rescued the phenotypic and chemoresistance effects resulting from LMAN2 modulation. Epistasis experiments confirmed that LMAN2-mediated chemoresistance strictly depends on SCD function.
    CONCLUSIONS: LMAN2 is a robust prognostic biomarker that promotes breast tumor growth and anthracycline resistance by enabling SCD-dependent lipid desaturation. Therapeutic targeting of the LMAN2/SCD axis represents a promising strategy to overcome chemoresistance in breast cancer.
    Keywords:   LMAN2 ; ADM; SCD; breast cancer; cholesterol homeostasis
    DOI:  https://doi.org/10.1186/s13058-026-02343-3
  6. Pharmacol Res. 2026 Jul 06. pii: S1043-6618(26)00249-5. [Epub ahead of print]231 108334
    Loss of ETV4 triggers PPM1E downregulation and AMPK-ULK1-dependent autophagy to promote intrinsic trametinib resistance in breast cancer.
    Xiaodong Liu, Su Hyeon Yu, Jiyoon Kang, Ji Won Kim.
      Trametinib, a selective MEK1/2 inhibitor, is approved for melanoma, BRAF-mutant non-small cell lung cancer, and thyroid cancer. Its favorable pharmacologic profile has prompted broader evaluation across cancers driven by MAPK/ERK signaling. However, its efficacy as monotherapy in breast cancer remains limited due to intrinsic resistance. Here, we investigated the molecular basis of intrinsic trametinib resistance and sought strategies to enhance therapeutic response. Trametinib responsiveness was associated with ETV4 expression. Notably, trametinib reduced ETV4 expression in three cell lines with high basal ETV4 expression (MDA-MB-453, SKBR3, and T47D). Consistent with ERK/MAPK-dependent regulation of ETV4, trametinib-mediated MEK inhibition was associated with stabilization of Capicua (CIC), a transcriptional repressor of ETV4, thereby suppressing ETV4 expression. In ETV4-high cells, trametinib-induced ETV4 downregulation promoted autophagic flux. Mechanistically, trametinib treatment and ETV4 silencing induced AMPK Thr172 phosphorylation, leading to ULK1 Ser555 phosphorylation and mTOR inhibition, thereby activating protective autophagy. RNA-seq analysis revealed that trametinib treatment and ETV4 knockdown produced highly overlapping transcriptomic profiles. Notably, trametinib reduced the expression of PPM1E, a phosphatase that negatively regulates AMPK, along with canonical MAPK effector genes. ChIP-PCR analysis and public ChIP-seq data demonstrated that ETV4 directly occupies the PPM1E promoter region and enhances PPM1E transcription, whereas trametinib-induced ETV4 suppression reduced PPM1E expression, limiting AMPK dephosphorylation and thereby promoting AMPK activation. Pharmacological inhibition of autophagy using chloroquine (CQ) or 3-methyladenine (3-MA) enhanced trametinib-induced apoptosis in vitro and suppressed T47D xenograft tumor growth in vivo. Collectively, our findings define a CIC-ETV4-PPM1E-AMPK signaling cascade through which trametinib-induced ETV4 downregulation drives AMPK-ULK1-dependent protective autophagy, thereby conferring a survival advantage in ETV4-high breast cancer. Autophagy blockade restores trametinib sensitivity and induces apoptosis, supporting a combinatorial strategy to improve MEK1/2-targeted therapy.
    Keywords:  Autophagy; Breast cancer; ETS variant transcription factor 4 (ETV4); Trametinib
    DOI:  https://doi.org/10.1016/j.phrs.2026.108334
  7. Eur J Pharmacol. 2026 Jul 09. pii: S0014-2999(26)00613-8. [Epub ahead of print] 179131
    Targeting Lipid Metabolism Enzymes in Breast Cancer: Mechanistic Basis and Therapeutic Vulnerabilities.
    Xinpeng Li, Hua Hao.
      Breast cancer constitutes a metabolically heterogeneous disorder wherein enzymes associated with lipid metabolism are instrumental in tumor progression, adaptation to the microenvironment, and therapeutic response. Beyond their catalytic roles in fatty acid, cholesterol, and phospholipid metabolism, these enzymes may function as regulatory nodes linking lipid flux to membrane remodeling, lipid peroxide detoxification, autophagy-dependent recycling, epithelial-mesenchymal plasticity, tumor-macrophage crosstalk, epigenetic stabilization, and multidrug resistance (MDR). This review adopts a subtype-aware, node-based framework to analyze lipid metabolic enzymes as context-dependent drivers of malignant phenotypes and treatment resistance. Furthermore, pharmacological strategies targeting lipid metabolic pathways-including fatty acid synthase (FASN) inhibition, ferroptosis induction, blockade of fatty acid oxidation, modulation of cholesterol metabolism, and interference with lipid uptake-are examined. The majority of these strategies are currently at preclinical or early translational stages, encountering significant challenges such as toxicity, metabolic compensation, subtype heterogeneity, and inadequate biomarker-guided patient selection. This review emphasizes lipid-metabolism enzymes as potential therapeutic vulnerabilities and underscores the necessity for mechanistic validation, rational combination therapies, and biomarker-driven metabolic stratification in breast cancer.
    Keywords:  biomarker-guided therapy; breast cancer; ferroptosis; lipid metabolism enzymes; multidrug resistance; therapeutic vulnerability; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.ejphar.2026.179131
  8. Mol Cell Biol. 2026 Jul 04. 1-31
    Transcription Factors in Breast Cancer Oncogenesis and Progression.
    Lianna Fiore, Zhijie Li, Collin Montgomery, Audrey Coleman, Colin Kenny, Ronald J Weigel.
      Gene expression regulated through a set of transcription factors orchestrates the physiologic processes that drive mammary gland development, breast cancer oncogenesis, and breast cancer progression. This review highlights recent progress in our understanding of how transcriptional regulators mediate mammary gland development, mammary oncogenesis and maintenance of breast cancer stem cells, breast cancer phenotype, metastasis, and efforts to target transcription factors as a therapeutic approach in breast cancer.
    Keywords:  Breast cancer; cancer stem cell; hormone response; mammary gland development; mammary oncogenesis; metastasis; transcription
    DOI:  https://doi.org/10.1080/10985549.2026.2694520
  9. Discov Oncol. 2026 Jul 10.
    Cancer-associated adipocytes promote breast cancer progression by upregulating miR-106b-3p to target SLK.
    Xiaomei Zhou, Jun Xiao, Zihui Yang, Ning Zeng, Haibin Wu, Jun Zhang, Yiping Wu.
       PURPOSE: Adipocytes are the most abundant primary stromal cells in breast cancer (BC). Cancer-associated adipocytes (CAAs) driven by cancer cells are considered important regulators in the BC tumor microenvironment. However, the specific mechanism underlying the interplay of CAAs and BC cells remains unclear.
    METHODS: We obtained CAAs by co-culturing adipocytes and MDA-MB-231 cells. RNA sequencing of MDA-MB-231 cells cultured in CAA-conditioned medium (CAA-CM) identified miR-106b-3p. We down-regulated miR-106b-3p expression in BC cells and assessed proliferation, migration, and invasion in vitro. In allograft and lung metastasis mouse models, we tested whether the tumor-promoting effects of CAA-CM could be counteracted by a miR-106b-3p inhibitor. Dual-luciferase assay and rescuing assay were used to reveal the functional target.
    RESULTS: CAAs exhibited a fibroblast-like appearance with reduced lipid droplets and decreased expression of mature adipocyte markers. miR-106b-3p was selected as a candidate miRNA from exploratory profiling and was further validated as a contributor to CAA-CM-associated malignant phenotypes in BC cells. Silencing miR-106b-3p suppressed BC cell proliferation, migration, and invasion in vitro. In allograft and lung metastasis models, the tumor-promoting effects of CAA-CM were counteracted by a miR-106b-3p inhibitor. Ste20-like kinase (SLK) was confirmed as the functional target of miR-106b-3p.
    CONCLUSION: We confirmed that CAAs promoted the proliferation, migration, invasion, and in vivo lung metastasis of BC cells by upregulating miR-106b-3p, which targeted and inhibited SLK expression. These effects were accompanied by increased PI3K/AKT phosphorylation, suggesting a potential association between the miR-106b-3p/SLK axis and PI3K/AKT pathway activation.
    Keywords:   miR-106b-3p ; Breast cancer; Cancer-associated adipocytes; Metastasis; Ste20-like kinase
    DOI:  https://doi.org/10.1007/s12672-026-05553-5
  10. Cell Rep. 2026 Jul 08. pii: S2211-1247(26)00708-4. [Epub ahead of print]45(7): 117630
    Distinct metabolic dependency on BCAA defines cancer stemness and malignancy in human triple-negative breast cancer.
    Kenkyo Matsuura, Ririko Shinonaga, Mizuki Yamamoto, Yoshiki Yamamoto, Hsin Chen, Ayaka Maeno, Kayo Okuda, Haruki Inoue, Sota Imotani, John Glushka, Koji Miki, Yukako Watanabe, Mamoru Takada, Hironori Kaji, Jun-Ichiro Inoue, Ayuna Hattori, Hiromi Imamura, Takahiro Ito.
      Triple-negative breast cancer (TNBC) lacks effective molecularly targeted therapies. Here, we identify branched-chain amino acid (BCAA) metabolism as a selective vulnerability in human TNBC, particularly in the claudin-low subtype. TNBC cells show greater dependence on BCAAs than other breast cancer subtypes, and intracellular BCAA levels are heterogeneous within tumors in vivo. Cells with high BCAA levels exhibit enhanced sphere formation and cancer stem cell potential in xenograft models. BCAT1, a cytoplasmic BCAA aminotransferase, is upregulated in claudin-low TNBC and enables tumor growth by promoting BCAA production from branched-chain ketoacids. BCAT1 knockdown impairs TNBC growth in vivo, and high BCAT1 expression predicts poor prognosis in patient cohorts. Conversely, BCAA catabolism via the BCKDH complex is suppressed in TNBC, and reactivation of BCKDH by BCKDK knockout blocks clonogenic growth. These findings reveal BCAA metabolic balance as a key regulator of TNBC stemness and malignancy.
    Keywords:  CP: cancer; TNBC; branched-chain amino acid; claudin-low; metabolic vulnerability; metabolite imaging
    DOI:  https://doi.org/10.1016/j.celrep.2026.117630
  11. Breast Cancer Res Treat. 2026 Jul 08. pii: 2. [Epub ahead of print]218(1):
    mRNA and protein expression of fetal insulin receptor in breast cancer cell lines and tissues.
    Xihong Zhang, Albert Barrios, LeeAnn Higgins, Todd Markowski, Kevin Murray, Bruce Witthuhn, Tzu-Yi Yang, Douglas Yee.
       BACKGROUND: The insulin receptor (IR) is expressed in breast cancer cells and plays a role in regulating tumor biology. There are two IR isoforms generated from the same gene. Alternate splicing with exclusion or inclusion of exon 11 accounts for the two isoforms. The exon 11 excluded isoform (IR-A) is expressed during fetal development while the full-length adult IR (IR-B) is the primary form expressed during adult life. This splice variant results in a 12 amino acid variation in peptide sequence. Breast cancer cells overexpress IR-A with an increased IR-A: IR-B ratio. Most of these data were obtained by examining mRNA expressions.
    METHODS: In this work, we examined over 40 breast cancer cell lines and patient tumor samples for mRNA expression of the IR isoforms. Further we used mass spectrometry to evaluate IR-A protein expression.
    RESULTS: Most breast cancer cell lines and tissues overexpress IR-A compared to IR-B. Mass spectrometry analysis demonstrated IR-A protein expression in the Du4475 cell line which has a high level of IR-A mRNA expression.
    CONCLUSION: IR-A mRNA is frequently expressed in breast cancer cells. To our knowledge, this is the first demonstration of IR-A protein expression. Thus, IR-A mRNA and protein expression demonstrate a potential role for this insulin receptor isoform in breast cancer biology.
    Keywords:  Adult form of insulin receptor; Breast cancer; Fetal form of insulin receptor; Insulin receptor; Mass spectrometry; mRNA expression
    DOI:  https://doi.org/10.1007/s10549-026-08018-z
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