bims-merabr 2026-09-06 papers

bims-merabr

Biomed News

on Metabolic rewiring in aggressive breast cancer

Issue of 2026–09–06
six papers selected by
Barbara Mensah Sankofi, University of Oklahoma Health Sciences Center

FOXA1 transcriptionally upregulates LMAN2 to promote breast cancer progression.
TRIB3 promotes triple-negative breast cancer metastasis by restricting lipophagy through the PI3K/AKT/mTOR signaling pathway.
Estrogen-related receptor α promotes breast cancer cell migration and invasion by activating transforming growth factor β signaling.
Current and Future Perspectives on Adipo-Oncology: Roles of Adipocytes in Local and Systemic Tumor Regulation.
Lysyl oxidase inhibition disrupts mitochondrial homeostasis to create vulnerability to ferroptosis in TNBC.
Epigenetic Reactivation of TNFRSF19 Suppresses Mitophagy and Sensitizes Triple-Negative Breast Cancer to Doxorubicin.

Tissue Cell. 2026 Aug 22. pii: S0040-8166(26)00578-1. [Epub ahead of print]104(Pt 2): 103883

FOXA1 transcriptionally upregulates LMAN2 to promote breast cancer progression.

Zhitao Zhang, Shaoyun Wang, Haifeng Sun, Yinping Yu.

   BACKGROUND: Breast cancer (BC), the most widespread malignancy in women globally, is characterized by complex and heterogeneous mechanisms. Lectin, mannose binding 2 (LMAN2), a potential oncogene highly expressed in BC, is linked to poor prognosis. The transcription factor forkhead box protein A1 (FOXA1) is often overexpressed in BC and tied to malignant phenotypes, but how it regulates LMAN2 to influence BC progression remains unclear.
METHODS: LMAN2 expression in BC and its association with patient prognosis were analyzed via the GEPIA database. mRNA and protein levels were detected by qRT-PCR and Western blot. Cell proliferation, angiogenesis, invasion/migration, and apoptosis were evaluated using EdU, tube formation assay, Transwell, and flow cytometry. The ferroptosis status of cells was assessed by detecting ferroptosis-related indicators. The transcriptional regulatory effect of FOXA1 on LMAN2 was verified using JASPAR database, chromatin immunoprecipitation (ChIP), and dual-luciferase reporter assays. The in vivo effect of the FOXA1/LMAN2 axis on BC growth was validated using a nude mouse xenograft model, and related protein expression was detected by immunohistochemistry (IHC).
RESULTS: LMAN2 was upregulated in BC, with high expression linked to poor survival. Silencing LMAN2 was associated with reduced BC cell proliferation, migration, invasion, and angiogenesis, concomitant with increased ferroptosis and apoptosis. FOXA1 binding sites were identified in the LMAN2 promoter; FOXA1 directly bound to this region to enhance LMAN2 transcription, and FOXA1 knockdown reduced LMAN2 expression. FOXA1 overexpression enhanced BC cell malignancy and suppressed ferroptosis, with these effects reversed by concurrent LMAN2 silencing. In vivo, FOXA1 knockdown restrained xenograft tumor growth, and this effect was reversed by concurrent LMAN2 overexpression.
CONCLUSION: FOXA1 bound to the LMAN2 promoter to enhance its transcription, thereby promoting BC progression at least partially through ferroptosis suppression and malignant phenotype induction.

Keywords:  Breast cancer; Ferroptosis; Forkhead box protein A1; Lectin; Mannose binding 2; Migration/invasion

DOI:  https://doi.org/10.1016/j.tice.2026.103883
Cell Signal. 2026 Aug 29. pii: S0898-6568(26)00510-3. [Epub ahead of print]148 112852

TRIB3 promotes triple-negative breast cancer metastasis by restricting lipophagy through the PI3K/AKT/mTOR signaling pathway.

Liqiong Ruan, Jianfeng Liu, Zirong Jiang.

   BACKGROUND: Lipophagy-driven metabolic reprogramming is increasingly recognized as a determinant of tumor progression. TRIB3, a key regulator of lipid metabolism, has been implicated in cancer aggressiveness, with elevated expression linked to poor outcomes in triple-negative breast cancer. Here, we investigated whether TRIB3 promotes TNBC metastasis through regulation of lipophagy and lipid metabolism.
METHODS: Public datasets (Oncomine, GEPIA, Kaplan-Meier Plotter) were analyzed to assess TRIB3 expression and its prognostic relevance in breast cancer. Immunohistochemistry and Western blotting validated TRIB3 expression in TNBC tissues and adjacent normal samples. Functional assays, including wound healing, Transwell migration, and EMT marker detection, were used to determine the effects of TRIB3 on cell migration and invasion. Subcutaneous xenograft and lung metastasis models were established in nude mice to evaluate its role in vivo. Potential upstream regulators were identified by dual-luciferase reporter assays, while downstream pathways were investigated using RNA sequencing, pathway enrichment, and functional annotation. The impact of TRIB3 on lipophagy was examined by transmission electron microscopy, immunofluorescence, and Western blotting, and further validated using autophagy inhibitors.
RESULTS: TRIB3 was significantly overexpressed in TNBC and correlated with unfavourable prognosis. Functional assays demonstrated that TRIB3 enhanced TNBC cell invasion and metastasis both in vitro and in vivo. Mechanistically, TRIB3 negatively regulated MSI2 protein expression and activated the PI3K/AKT/mTOR pathway, thereby disrupting lipid droplet redistribution and inhibiting lipophagy, which facilitated tumor migration and metastasis.
CONCLUSIONS: Our findings uncover a previously unrecognized mechanism by which TRIB3 regulates lipophagy to drive TNBC metastasis. We delineate the critical role of the TRIB3-MSI2 regulatory axis and its association with the PI3K/AKT/mTOR pathway, as well as the potential upstream involvement of FOXA1, in orchestrating this process. These results highlight TRIB3 as a central mediator of TNBC progression and suggest novel therapeutic strategies targeting lipophagy for this aggressive breast cancer subtype.

Keywords:  FOXA1; Lipophagy; MSI2; Metastasis; TNBC; TRIB3

DOI:  https://doi.org/10.1016/j.cellsig.2026.112852
Anticancer Drugs. 2026 Aug 14.

Estrogen-related receptor α promotes breast cancer cell migration and invasion by activating transforming growth factor β signaling.

Monica Prusty, Kartik Muduli, Jagannath Pradhan, Archana Priyadarshini Samal, Joytirmay Tripathy, K Sony Reddy, Selvakumar Elangovan.

  Breast cancer is a major cause of cancer-related mortality among women, and many patients eventually experience recurrence and progression to metastasis, despite advances in treatment. Estrogen-related receptor α (ERRα), an orphan nuclear receptor, is frequently overexpressed in aggressive breast cancer subtypes and is associated with poor prognosis and an increased risk of recurrence. This study aimed to investigate the role of transforming growth factor β (TGFβ) signaling in ERRα-mediated epithelial-mesenchymal transition (EMT), migration, and invasion in breast cancer cells. ERRα expression was modulated in breast cancer cells using XCT790-mediated inhibition, shRNA-mediated knockdown, and overexpression. Cell viability, clonogenicity, migration, invasion, EMT marker expression, and matrix metalloproteinase (MMP) activity were evaluated. TGFβ1 secretion and Smad signaling were also evaluated. XCT790-mediated inhibition or shRNA-mediated silencing of ERRα significantly reduced cell viability, migration, invasion, and MMP secretion in breast cancer cell lines, whereas ERRα overexpression upregulated migration, invasion, and MMP levels. ERRα suppression also upregulated the epithelial marker ZO-1 and downregulated mesenchymal markers, such as vimentin and β-catenin. This effect was associated with a significant decrease in TGFβ secretion, downregulation of TGFβ-mediated Smad signaling, and reduced expression of its downstream target ANGPTL4. These findings indicate that ERRα promotes EMT, migration, and invasion in breast cancer by upregulating TGFβ secretion and its signaling, underscoring its potential as a therapeutic target.

Keywords:  breast cancer; estrogen-related receptor α; invasion; matrix metalloproteinase; migration; transforming growth factor β

DOI:  https://doi.org/10.1097/CAD.0000000000001840
Pathol Int. 2026 Sep;76(9): e70170

Current and Future Perspectives on Adipo-Oncology: Roles of Adipocytes in Local and Systemic Tumor Regulation.

Shinya Sato.

  Adipose tissue has traditionally been regarded as an energy-storage organ; however, accumulating evidence indicates that adipocytes actively regulate cancer biology through local and systemic mechanisms. These findings have contributed to the emergence of adipo-oncology, an interdisciplinary field focused on interactions between adipose tissue and cancer. This review summarizes current evidence on the local and systemic roles of adipocytes in tumor progression and discusses how tissue heterogeneity and plasticity may influence these processes. Locally, adipocytes adjacent to tumors may be reprogrammed into cancer-associated adipocytes that promote tumor progression through enhanced lipolysis and inflammatory signaling, paracrine adipokine and cytokine secretion, local lipid transfer, and modulation of stromal and immune cell populations within the tumor microenvironment. Systematically, adipocytes may influence metabolic remodeling, epithelial-mesenchymal transition, invasion, metastasis, therapeutic resistance, and establishment of tumor-promoting niches. Additionally, adipocyte plasticity and epigenetic reprogramming have emerged as important determinants of adipocyte function during cancer progression. Collectively, these findings support a model in which adipocytes function as central regulators of cancer biology at local and systemic levels. A deeper understanding of the molecular basis of adipo-oncology may provide new insights into tumor progression and facilitate the development of metabolic, immunological, and epigenetic therapeutic strategies targeting adipose tissue.

Keywords:  adipokines; adipose tissue; cancer‐associated adipocyte; extracellular vesicles; lipid metabolism; obesity; tumor microenvironment

DOI:  https://doi.org/10.1111/pin.70170
Cell Rep Med. 2026 Aug 31. pii: S2666-3791(26)00432-5. [Epub ahead of print] 103015

Lysyl oxidase inhibition disrupts mitochondrial homeostasis to create vulnerability to ferroptosis in TNBC.

Ozge Saatci, Burge Ulukan, Metin Cetin, Hellen Kuasne, Constanza Martinez, Elif Percin, Natalia Oleinik, Matthew T Savoca, Ali Nehme, Aldo Hernández-Corchado, Evelyn Zavacky, Kukkamudi Sreenivas, Abdol H Rezaeian, Jennifer R Bethard, Jean-Sebastien Anoma, Ozlem Sener Sahin, Adriana Aguilar-Mahecha, Marguerite Buchanan, Mertkaya Aras, Genevieve DeBlois, Mark Basik, Elizabeth G Hill, Lauren E Ball, Chintada Nageswara Rao, Campbell McInnes, Yasser Riazalhosseini, Hamed S Najafabadi, John J Lemasters, Besim Ogretmen, Morag Park, Ozgur Sahin.

  High metabolic heterogeneity and plasticity of triple-negative breast cancer (TNBC) contribute to therapy resistance, necessitating identification of therapeutic vulnerabilities. Here, we identify non-canonical functions of the extracellular matrix (ECM) remodeler, lysyl oxidase (LOX), in regulating glucose metabolism and mitochondrial homeostasis and show that inhibiting LOX generates targetable vulnerability to ferroptosis. Mechanistically, LOX interacts with PARKIN and its upstream kinase PINK1, which we identified as a substrate of LOX. LOX-mediated PINK1 oxidation suppresses PARKIN phosphorylation, stabilizing hypoxia-inducible factor 1-alpha (HIF-1α) and increasing glycolysis. Concomitantly, LOX inhibits PARKIN-mediated mitophagy and maintains mitochondria-ER contacts through VDAC1 stabilization, while the LOX-HSP90 complex promotes mitochondrial Ca2+ transport and ATP production. Inhibiting LOX suppresses glycolysis, disrupts mitochondrial dynamics, reduces OXPHOS and GPX4/FSP1, and induces compensatory DHODH activity. Our "one-two punch" approach combining LOX inhibition with clinical DHODH inhibitor suppresses tumor growth in vivo in chemo-free setting. Notably, LOX protein correlates with HIF-1α/GLUT1/GPX4 in TNBC patient tumors, supporting its clinical relevance.

Keywords:  DHODH; LOX; MERCS; TNBC; ferroptosis; glucose metabolism; lysyl oxidase; mitochondria-ER contacts; mitophagy

DOI:  https://doi.org/10.1016/j.xcrm.2026.103015
Adv Sci (Weinh). 2026 Aug 31. e77529

Epigenetic Reactivation of TNFRSF19 Suppresses Mitophagy and Sensitizes Triple-Negative Breast Cancer to Doxorubicin.

Shiyang Liu, Chenguang Liu, Weihong Zheng, Xiaofei Tong, Zhengwei Gui, Zonghong Lu, Sun Ieong, Lin Zhang.

  Doxorubicin remains an important component of chemotherapy for triple-negative breast cancer (TNBC), yet chemoresistance severely limits its clinical efficacy. Here, we identify Tumor necrosis factor receptor superfamily member 19 (TNFRSF19) as an epigenetically silenced gene that critically regulates doxorubicin response. Integrative analyses of The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and clinical cohorts reveal that high TNFRSF19 expression predicts superior pathological complete response and improved survival in doxorubicin-treated TNBC patients. Mechanistically, TNFRSF19 binds the kinase domain of TGFBR1 via its intracellular domain, disrupting TGFBR1-SMAD3 complex formation and thereby inhibiting SMAD3 phosphorylation, nuclear translocation, and transcriptional activation of PTEN-induced putative kinase 1 (PINK1). This suppresses PINK1/Parkin-mediated mitophagy, contributing to mitochondrial dysfunction, reactive oxygen species (ROS) accumulation, and amplified DNA damage upon doxorubicin treatment. Notably, TNFRSF19 is downregulated in TNBC due to DNA hypermethylation, and decitabine restores its expression via promoter demethylation, thereby enhancing the therapeutic efficacy of doxorubicin in vitro and in vivo. Collectively, these findings establish TNFRSF19 as a critical epigenetic regulator of mitophagy, highlighting its potential as a predictive biomarker for doxorubicin response and a therapeutic target for sensitizing TNBC to doxorubicin.

Keywords:  DNA methylation; TNFRSF19; doxorubicin; mitophagy; triple‐negative breast cancer

DOI:  https://doi.org/10.1002/advs.77529