bims-merabr 2026-07-05 papers

bims-merabr

Biomed News

on Metabolic rewiring in aggressive breast cancer

Issue of 2026–07–05
ten papers selected by
Barbara Mensah Sankofi, University of Oklahoma Health Sciences Center

ATP5F1B promotes breast cancer progression through ERK associated metabolic reprogramming.
Adapalene inhibits the activity of CD44, a cancer stem cell biomarker in Triple negative breast cancer.
SDC1 Knockdown Suppresses Malignant Phenotypes of Breast Cancer by Modulating the MAPK Signaling Pathway.
Glucagon-Like Peptide-1 Receptor Agonists in Breast Cancer: Metabolic, Clinical, and Survivorship Implications.
Adipocyte Pten Inhibition Improves Metabolic Health Associated with Expanded Lipid Storage Capacity and Reduced Inflammation.
MiR-139 modulates CD8+ T cells exhaustion by targeting CD28 in breast cancer.
TMEM216 inhibits breast cancer lung metastasis by modulating IGF1R-IRS4 signaling pathway.
DNA methylation-mediated silencing of STAT5A drives breast cancer metastasis via dual regulation of EMT and immunosuppressive microenvironment.
Microenvironmental Cues That Regulate Cancer Cell Dormancy in Estrogen-Receptor Positive and Triple-Negative Breast Cancer Cell Lines.
Genetic regulatory axis between AGR2 and ESR1 promotes breast cancer progression.

Mol Biol Rep. 2026 Jul 03. pii: 1096. [Epub ahead of print]53(1):

ATP5F1B promotes breast cancer progression through ERK associated metabolic reprogramming.

Xuan Lu, Ruiqing Li, Jiejing Chen, Qiwang Zhou.

   BACKGROUND: To systematically evaluate the prognostic significance of mitochondrial ATP synthase subunits in breast cancer and to investigate the clinical relevance, biological function, and metabolic role of ATP5F1B in breast cancer progression.
METHODS: Publicly available breast cancer transcriptomic profiles with matched clinical annotations were analyzed in a family-level screen of mitochondrial ATP synthase subunits. ATP5F1B was prioritized and was evaluated by loss- and gain-of-function assays in AU565 and HCC1428 cells. Differential expression and functional enrichment analyses were performed, and metabolic activity was assessed by extracellular acidification rate. Key genes and proteins were validated by qRT-PCR and Western blotting.
RESULTS: ATP5F1B was upregulated in tumor tissues and emerged as the only screened F1 subunit consistently associated with survival. High ATP5F1B expression was linked to poorer overall survival, disease-specific survival, and progression-free interval, and correlated with clinicopathologic features, including age, estrogen receptor status, and PAM50 subtypes, with enrichment in Luminal B and HER2-enriched tumors. ATP5F1B knockdown reduced proliferation and clonogenic growth, whereas ATP5F1B overexpression enhanced cell growth and was accompanied by decreased BAX and increased BCL-2. Transcriptomic analyses identified ATP5F1B-associated gene expression programs with significant GO/KEGG enrichment. Metabolically, ATP5F1B depletion reduced glycolytic activity and downregulated HK2, PKM2, LDHA, CHPT1, LPCAT1, and ERK-related transcriptional expression.
CONCLUSIONS: ATP5F1B is associated with poor prognosis and promotes breast cancer cell growth, potentially through metabolic regulation.

Keywords:  ATP5F1B; Breast cancer; Metabolic regulation; Prognosis

DOI:  https://doi.org/10.1007/s11033-026-12272-1
Mol Biol Rep. 2026 Jul 03. pii: 1089. [Epub ahead of print]53(1):

Adapalene inhibits the activity of CD44, a cancer stem cell biomarker in Triple negative breast cancer.

Shazia Sofi, Nusrat Jan, Gowhar Masoodi, Shariqa Jan, Syed Nisar Ahmad, Umar Mehraj, Manzoor Ahmad Mir.

   BACKGROUND: One of the crucial steps in the development of tumor metastasis is tumor cell invasion. This stage initiates a sequence of molecular interactions that enable invasive cells to adhere to the extracellular matrix (ECM) through the activity of cell adhesion molecules (CAMs). The primary cell surface receptor for ECM components is CD44. High levels of CD44 are necessary for breast cancer stem cells (BCSCs) to retain the multipotency of the BCSC population.
AIM: This study examines methods for focusing on tumour cells that overexpress CD44 and provides a thorough summary of CD44's function in the development of breast cancer.
METHODS: Using in vitro models, we evaluated the therapeutic potential of Adapalene, a repurposed drug that is often used to treat acne. Western blotting analysis was used to check the expression of resistance markers in Paclitaxel-resistant cells. The ability of Adapalene to target and exhibit CD44 expression was examined using immunocytochemistry methods. Additionally, we used an in silico/docking technique to assess Adapalene's interaction with CD44.
RESULTS: According to our findings, Adapalene selectively kills TNBC cells rather than non-TNBC cells, particularly in the 4T1 model. Interestingly, drug-resistant produced MDA-MB-231 cells exhibited a 298-fold increase in ic50 value in comparison to the parental MDA-MB-231 cells. The findings showed that Adapalene targets CD44, a crucial stemness biomarker, to decrease the stemness traits of drug-resistant cells.
CONCLUSION: Overall, this study highlights how CD44 overexpression accelerates the growth of breast cancer and transforms drug-resistant cells into stem cells, and that targeting CD44 with Adapalene may significantly enhance therapy results and defer the onset of drug resistance in breast cancer patients.

Keywords:  Adapalene; Breast Cancer; Cytotoxicity; Drug Resistance; Metastasis; Stemness; Triple negative breast cancer

DOI:  https://doi.org/10.1007/s11033-026-12050-z
Cancer Med. 2026 Jul;15(7): e72016

SDC1 Knockdown Suppresses Malignant Phenotypes of Breast Cancer by Modulating the MAPK Signaling Pathway.

Weixun Lin, Xiuying Chen, Juan Zou, Yanxian Chen, Zeqi Ji, Zhiyang Li, Bo Xu.

  Breast cancer remains a leading cause of morbidity and mortality among women worldwide, necessitating in-depth research into its molecular mechanisms to improve prognosis and treatment strategies. This study investigates the expression profile and functional role of heparan sulfate proteoglycan Syndecan-1 (SDC1) in breast cancer progression, with a focus on its downstream signaling pathways. Utilizing bioinformatics analysis of datasets from the GEO and TCGA databases, we identified significantly elevated SDC1 expression in breast cancer tissues compared to normal counterparts, correlating with advanced tumor stage, lymph node metastasis, and poor survival outcomes. Clinical sample validation through RT-qPCR and Western blot confirmed SDC1 overexpression in breast cancer tissues and cell lines. Functional experiments, including SDC1 knockdown via lentiviral infection, revealed that reduced SDC1 expression markedly impairs breast cancer cell proliferation, migration, and angiogenesis, as evidenced by CCK-8, EdU, wound healing, Transwell, and tube formation assays. Mechanistically, transcriptome sequencing and Western blot analysis demonstrated that SDC1 knockdown significantly suppressed the phosphorylation of key MAPK pathway components (ERK1/2, JNK, and p38). Rescue experiments using the MAPK agonist C16-PAF effectively reversed the inhibitory effects of SDC1 knockdown on cell proliferation, migration, and angiogenesis. Furthermore, in vivo xenograft models confirmed that SDC1 knockdown suppressed tumor growth and reduced microvessel density, while C16-PAF treatment partially reversed these effects. Collectively, our findings demonstrate that SDC1 promotes breast cancer progression by activating the MAPK signaling pathway, highlighting SDC1 as a potential prognostic biomarker and therapeutic target in breast cancer.

Keywords:  MAPK signaling pathway; SDC1; breast cancer; malignant phenotypes; prognostic markers

DOI:  https://doi.org/10.1002/cam4.72016
JCO Oncol Pract. 2026 Jul 01. OP2600061

Glucagon-Like Peptide-1 Receptor Agonists in Breast Cancer: Metabolic, Clinical, and Survivorship Implications.

Jasmin Hundal, Marguerite Linz, Samatha Anikreddy, Shivangi Sengupta, Keren Zhou, Baidehi Maiti.

Breast cancer is increasingly recognized as an obesity-associated disease, with obesity linked to higher risk of postmenopausal estrogen receptor-positive disease and adverse outcomes across stages. Adipose tissue dysfunction in chronic energy excess drives a tumor-supportive milieu: Crown-like structures and macrophage inflammation increase local aromatase and estrogen production, while elevated free fatty acids contribute to hyperinsulinemia and IGF-1 signaling with activation of PI3K/Akt/mTOR and MAPK pathways; leptin is increased and adiponectin reduced, amplifying proliferative and inflammatory cues. Standard breast cancer therapies can further worsen weight gain and insulin resistance, increasing symptom burden, reducing quality of life, and potentially compromising treatment delivery. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are highly effective agents for obesity and type 2 diabetes that improve glycemic control and reduce cardiovascular risk, prompting growing use in patients with breast cancer. Available breast cancer-specific data are largely retrospective and suggest clinically meaningful but attenuated weight loss compared with pivotal obesity trials, with concurrent aromatase inhibitor or tamoxifen use associated with smaller reductions. No unique breast cancer toxicities have been identified to date, to our knowledge, but clinicians should monitor GI tolerability, hydration and nutrition, and changes in body composition, including potential lean mass loss that may be mitigated with resistance training and adequate protein intake. Clinical considerations include changes in breast imaging during rapid weight loss (including possible increases in mammographic density), uncertainty regarding perioperative use in reconstructive surgery, and careful attribution of GI symptoms to GLP-1RA therapy versus chemotherapy. Studies also suggest potential survivorship benefits relevant to lymphedema and cardio-oncology, although causality is unproven. Prospective cancer-specific trials and implementation studies are needed to define safety; optimal timing; patient selection; and effects on oncologic outcomes, function, and quality of life.

DOI: https://doi.org/10.1200/OP-26-00061
bioRxiv. 2026 Jun 25. pii: 2026.06.20.733549. [Epub ahead of print]

Adipocyte Pten Inhibition Improves Metabolic Health Associated with Expanded Lipid Storage Capacity and Reduced Inflammation.

Yumei Zhou, Yubo Wang, Jessica E Meerson, Zhiyong Cheng, Shihuan Kuang, Feng Yue.

Adipose tissue dysfunction drives obesity-associated insulin resistance, but whether expanding adipocyte lipid storage can improve metabolic health remains unclear. Here, we generated adipocyte-specific Pten knockout mice ( Pten AKO ) using Adipoq -Cre to determine how chronic Pten loss affects adipose tissue remodeling and systemic metabolism. Pten AKO mice exhibit increased adiposity and adipocyte hypertrophy under chow and high-fat diet feeding, yet showing lower blood glucose and insulin levels, enhanced insulin sensitivity, and reduced hepatic lipid accumulation during basal growth and diet-induced obesity without systemic metabolic deterioration. Despite lipid enrichment in brown adipose tissue, Pten-deficient adipocytes maintain UCP1 expression, OXPHOS protein abundance, and mitochondrial ultrastructure. Transcriptomic analysis of inguinal white adipose tissue reveals activation of adipogenesis, lipid metabolism, insulin response, oxidative phosphorylation, lipid storage, vascular and extracellular matrix pathways, together with suppression of immune and inflammatory programs. Mechanistically, Pten deficiency increases Cav1 expression, caveolae abundance, collagen expression, and extracellular matrix remodeling, suggesting coordinated structural adaptation to support adipocyte expansion. These findings demonstrate that adipocyte Pten deficiency promotes metabolically healthy adipose expansion by enhancing lipid storage capacity, preserving adipocyte function, and reducing inflammation.

DOI: https://doi.org/10.64898/2026.06.20.733549
iScience. 2026 Jul 17. 29(7): 116411

MiR-139 modulates CD8+ T cells exhaustion by targeting CD28 in breast cancer.

Jianrong Chen, Haiyong Zhang, Yanting Lv, Xiufang Li, Mengjun Hu.

  miR-139 acts as a tumor suppressor in breast cancer cells, yet its role within the tumor immune microenvironment (TIME) remains unclear. This study explores the dual functions of miR-139 in both tumor and immune cells, particularly its effect on CD8+ T cell function and chemokine-mediated immune recruitment. Bioinformatics analysis using TCGA and GEO data identified miR-139 as differentially expressed in breast cancer. Using samples from 32 patients, we detected elevated miR-139 levels in tumor-infiltrating CD8+ T cells compared with adjacent normal tissues. Further experiments confirmed that miR-139 directly targets CD28, leading to its downregulation. Concurrently, increased expression of exhaustion markers PD-1 and TIGIT was observed. Moreover, tumors with high miR-139 expression showed upregulation of T-cell-recruiting chemokines CX3CL1, CXCL12, and CXCL14. These results demonstrate that miR-139 promotes CD8+ T cell exhaustion via suppression of CD28 and facilitates chemokine-mediated T cell recruitment, highlighting its immunosuppressive role in breast cancer.

Keywords:  Cancer; Cell biology; Immunology

DOI:  https://doi.org/10.1016/j.isci.2026.116411
Nat Commun. 2026 Jul 01.

TMEM216 inhibits breast cancer lung metastasis by modulating IGF1R-IRS4 signaling pathway.

Yingying Wang, Xinyang Bai, Zhiyuan Du, Jiaxi Dong, Luoyang Wang, Shenglong Xu, Xiaopeng Li, Junnan Zhou, Jiahui Zhou, Zirui Xu, Xi Kuang, Xiaoyang Sun, Qianqian Gong, Ling Su, Xiangguo Liu.

Breast cancer (BC) metastasis remains a major cause of mortality, yet the molecular mechanisms driving this process are incompletely understood. This study identifies TMEM216, a transmembrane protein implicated in ciliary homeostasis, as a suppressor of lung metastasis in BC. Using mammary-specific Tmem216 knockout mice, we demonstrate that Tmem216 deficiency promotes lung metastasis without affecting primary tumor proliferation. Clinical analyses reveal reduced TMEM216 expression in metastatic lesions and aggressive cell lines, correlating with poor patient distant metastasis-free survival. Mechanistically, TMEM216 interacts with IGF1R and binds to IRS4 via the conserved K79-D1049 interaction, disrupting the IGF1R-IRS4 complex formation and suppressing IGF pathway activation. Rescue experiments in vitro and in vivo confirm that TMEM216-mediated metastasis inhibition depends on IGF signaling modulation. Tissue microarray analyses further establish an inverse correlation between TMEM216 levels and IGF1R phosphorylation in BC patients, with low TMEM216 expression associated with advanced metastasis. These findings delineate TMEM216 as a critical regulator of the IGF1R-IRS4 axis, offering therapeutic opportunities for targeting metastatic BC.

DOI: https://doi.org/10.1038/s41467-026-75155-w
Oncogene. 2026 Jun 29.

DNA methylation-mediated silencing of STAT5A drives breast cancer metastasis via dual regulation of EMT and immunosuppressive microenvironment.

Xue Yang, Yuhang Su, Yushi Ying, Youyun Peng, Ruyuan Wang, Shaojie Xu, Yuxi Zhao, Xin Shu, Qiyue Peng, Xingrui Li, Yaying Du.

Signal transducer and activator of transcription 5 A (STAT5A) modulates breast cancer cell proliferation and metastasis, yet its epigenetic regulatory mechanisms and impacts on the tumor immune microenvironment (TIME) remain unclear. Here, we explored STAT5A's epigenetic traits, metastatic roles, and effects on tumor-associated immune cells via two mouse models (immunodeficient vs. immunocompetent) with metastasis established by tail vein injection or orthotopic tumorigenesis, flow cytometry to characterize immune cell subsets, cell co-cultures, clinical tissue analyses, and dCas9-TET1CD-mediated STAT5A promoter methylation intervention. Low STAT5A expression reduced tumor cell proliferation but enhanced migration/invasion, with in vivo metastatic capacity dependent on TIME. Tumors with low STAT5A expression grew slower and metastasized less in immunodeficient mice, but exhibited opposite phenotypes in immunocompetent cohorts. Mechanistically, STAT5A downregulation was associated with epithelial-mesenchymal transition (EMT), cytokine pathway remodeling, impaired T-cell cytotoxicity, and macrophage-associated immunosuppressive remodeling. Macrophage-derived LIF activated STAT5A phosphorylation via LIFR. Clinical samples showed sequentially increasing STAT5A promoter methylation and decreasing protein expression from normal tissues to primary/metastatic tumors. dCas9-TET1CD-mediated targeted demethylation restored STAT5A expression and reduced cell migration. These findings suggest that epigenetic silencing of STAT5A contributes to breast cancer metastasis through coordinated regulation of EMT-like plasticity and the TIME, and support further investigation of STAT5A reactivation or LIF-LIFR modulation as potential anti-metastatic strategies.

DOI: https://doi.org/10.1038/s41388-026-03849-y
Cancer Med. 2026 Jul;15(7): e72059

Microenvironmental Cues That Regulate Cancer Cell Dormancy in Estrogen-Receptor Positive and Triple-Negative Breast Cancer Cell Lines.

Jinesh Maniar, Pulkit Datt, Prerana P Dange, Vaishali Kailaje, Mithlesh Lakhera, Mansi Samarth, Tanuja Durve, Anushree Kadam, Khushboo A Gandhi, Sudeep Gupta.

The processes regulating cellular dormancy in tumor cells remain inadequately characterized. Further, there are very few models available that can recapitulate a dormancy-like phenotype in vitro. In this study, we investigated the role of microenvironmental cues in inducing a dormancy-like phenotype in estrogen receptor-positive (MCF-7) and triple-negative (MDA-MB-231) breast cancer cell lines. We characterized an in vitro model in distinct conditions defined hierarchically by the following: (a) normoxia or true hypoxia, (b) dishes coated with fibronectin or laminin or none, and (c) presence or absence of 10 ng/mL basic fibroblast growth factor (FGF-2) in the culture medium, added on day 0 of culture. Cells were cultured at clonogenic densities for 9 days (day -1, day 0, up to day +7). Cells were characterized for dormancy- like behavior using increased p-p38 and decreased p-ERK expression (dormant, p-p38High and p-ERKLow expression), reduced Ki67 expression, elevated p21 and p27 levels by immunofluorescence, absence of senescence using β-galactosidase staining and resistance to doxorubicin. Fibronectin or laminin were sufficient for the induction of a dormancy-like phenotype in MCF-7 cells under hypoxic conditions, whereas the addition of FGF-2 to fibronectin (but not laminin) could induce a dormancy-like phenotype under normoxic conditions. FGF-2 was required with laminin to induce dormancy in MDA-MB-231 cells under hypoxic conditions (FGF-2 plus fibronectin were unable to induce dormancy), whereas laminin or fibronectin alone were sufficient under normoxic conditions. Overall, we established culture conditions that recapitulate an in vitro breast cancer dormancy-like phenotype and reveal subtype-specific differences in dormancy regulation.

DOI: https://doi.org/10.1002/cam4.72059
PLoS One. 2026 ;21(7): e0351873

Genetic regulatory axis between AGR2 and ESR1 promotes breast cancer progression.

M Aiman Mohtar, Delphine Fessart, Chia Yuh Cai, Syazalina Zahari, Saiful Effendi Syafruddin, Muhammad-Redha Abdullah-Zawawi, Valerie Le Morvan, Said Taouji, Ted Hupp.

Anterior gradient protein 2 (AGR2), a member of the protein disulfide isomerase family, plays a critical role in endoplasmic reticulum proteostasis and has been implicated in breast cancer progression. However, the downstream regulatory programs and signaling pathways governed by AGR2 remain incompletely defined. Here, we employed CRISPR-Cas9-mediated knockout of AGR2 in breast cancer cells to systematically investigate the functional and transcriptional consequences of AGR2 loss. AGR2 depletion resulted in significant suppression of cell migration, invasion, and chemoresistance. Unbiased transcriptomic profiling by RNA sequencing revealed extensive differential gene expression, implicating AGR2 in receptor-mediated signaling, oxidative stress responses, and cell adhesion pathways. Protein-protein interaction network analysis identified several highly connected hub genes within the AGR2-regulated transcriptome, including estrogen receptor alpha (ESR1/ERα), cadherin 1 (CDH1), androgen receptor (AR), lymphocyte cell-specific protein-tyrosine kinase (LCK), S100 calcium binding protein P (S100P), parkin RBR E3 ubiquitin ligase (PRKN), and decay-accelerating factor (CD55). Notably, ERα emerged as a prominent node within this network, consistent with prior reports linking ERα and AGR2 biology. Integration with publicly available epigenomic datasets further supports a potential regulatory connection between ERα-associated chromatin landscapes and AGR2 expression. Together, these findings define AGR2-dependent transcriptional networks in breast cancer and identify ESR1-associated signaling as a key pathway perturbed upon AGR2 loss, providing a foundation for future mechanistic studies targeting this regulatory interaction.

DOI: https://doi.org/10.1371/journal.pone.0351873