bims-merabr 2026-03-22 papers

bims-merabr

Biomed News

on Metabolic rewiring in aggressive breast cancer

Issue of 2026–03–22
nine papers selected by
Barbara Mensah Sankofi, University of Oklahoma Health Sciences Center

IFFO1 inhibits breast cancer by coordinating mitochondrial fission and fatty acid synthesis via the LaminA/C-PGC1α axis.
The microbiome: a link between obesity and breast cancer risk.
ACE2 acts as a tumor suppressor in breast cancer by inhibiting progression via the TGF-β1/Smad pathway and potentiating immune checkpoint blockade.
HIF-1-regulated TPM3 links hypoxia to motility and invasion beyond the hypoxic fraction in triple-negative breast cancer.
Radiation-induced autophagy regulates fibroblast mitochondrial metabolism and crosstalk with triple-negative breast cancer cells.
SLAMF8 Promotes M2 Polarization of Macrophages and Enhances Breast Cancer Proliferation.
Targeting ZNF570 activates ferroptosis to reverse tamoxifen resistance in ER + breast cancer cells.
Androgen receptor localisation and protein interactions provide insight into steroid mediated metabolic shifts in endocrine resistant breast cancer.
Cancer-associated fibroblasts as key regulators of lipid metabolism in the tumour microenvironment.

Oncogenesis. 2026 Mar 17.

IFFO1 inhibits breast cancer by coordinating mitochondrial fission and fatty acid synthesis via the LaminA/C-PGC1α axis.

Huaxia Cai, Jianjun He.

Accumulating evidence indicates that mitochondrial dynamics are closely linked to the biological behaviors of tumor cells, with increased mitochondrial fission being recognized as a phenotype that promotes tumor growth. Although intermediate filament family orphan 1 (IFFO1) has been implicated in mitochondrial dynamics, its specific role and molecular mechanisms in regulating mitochondrial fission during breast cancer (BC) progression remain unclear. In this study, analysis of tumor and adjacent normal tissues from 30 BC patients revealed significant downregulation of IFFO1 in tumor tissues, and low IFFO1 expression predicted poor prognosis in patients. In vitro experiments demonstrated that IFFO1 overexpression suppressed the proliferation, invasion, and epithelial-mesenchymal transition (EMT) of BC cells by inhibiting mitochondrial fission and fatty acid synthesis. Mechanistically, IFFO1 interacts with LaminA/C to promote its expression, which subsequently upregulates PGC1α, thereby suppressing mitochondrial fission and fatty acid synthesis in BC cells. Consistent with this mechanism, both LaminA/C and PGC1α were downregulated in BC tissues. Silencing LMNA reversed the inhibitory effects of IFFO1 overexpression on mitochondrial fission and fatty acid synthesis, whereas overexpression of PGC1α effectively counteracted the consequences of LMNA knockdown. In vivo studies confirmed that upregulation of IFFO1 inhibited tumor growth in xenograft models and reduced lung metastasis in a lung metastasis mouse model. These findings underscore the significance of the IFFO1/LaminA/C/PGC1α pathway as a key regulator of mitochondrial fission and fatty acid synthesis during BC progression and highlight its potential as a therapeutic target for breast cancer.

DOI: https://doi.org/10.1038/s41389-026-00609-1
Front Microbiomes. 2024 ;3 1394719

The microbiome: a link between obesity and breast cancer risk.

Mohamed Gaber, Alana A Arnone, Pierre-Alexandre Vidi, Katherine L Cook.

  Globally, breast cancer is the leading cause of cancer incidence and mortality among all female cancers. Hereditary factors only account for 5-10% of breast cancers, highlighting the importance of non-hereditary factors, such as obesity. The increasing prevalence of obesity underscores the need to understand its contribution to breast cancer risk. Multiple mechanisms may mediate pro-carcinogenic effects of obesity, including altered adipokine levels, local and systemic inflammation, disruption of insulin and insulin-like growth factor signaling, increased estrogen levels, and alterations of the microbiome. In this review, we focus on the link between gut microbiome alterations and breast cancer risk in the context of obesity. First, we discuss how obesity influences the gut microbiome. Next, we describe the effect of such microbiome alterations on breast carcinogenesis, highlighting underlying molecular mechanisms. Finally, we review preclinical data on the interactions between host and bacteria, current challenges to study the obesity-microbiome connection, and future perspectives in this field.

Keywords:  MAMP signaling; breast cancer; inflammation; microbiome; obesity

DOI:  https://doi.org/10.3389/frmbi.2024.1394719
Biochim Biophys Acta Mol Basis Dis. 2026 Mar 13. pii: S0925-4439(26)00087-6. [Epub ahead of print]1872(5): 168224

ACE2 acts as a tumor suppressor in breast cancer by inhibiting progression via the TGF-β1/Smad pathway and potentiating immune checkpoint blockade.

Jianya Cai, Feijing Wu, Ying Wang, Yanhong Lan, Hongwei Cheng, Shuangta Xu.

  Angiotensin-converting enzyme 2 (ACE2) is acknowledged for its crucial function as a receptor in pneumonia. However, emerging evidence suggests that ACE2 also plays a significant role in tumor progression, but its regulatory mechanisms in breast cancer remain unclear. This study aims to elucidate the clinical significance and underlying mechanism of ACE2 in breast cancer. Our findings demonstrate that ACE2 expression is significantly downregulated in breast cancer tissues compared to adjacent normal tissues, exhibiting subtype-specific patterns: most pronounced in Luminal A and Luminal B, modest in Basal-like, and unchanged in Her2-positive tumors. ACE2 downregulation in these subtype-specific breast cancers may indicate a poor prognosis. Furthermore, this study identified that ACE2 is positively correlated with infiltration of various immune cells, especially CD4+ T cells and CD8+ T cells, shaping an immune-active microenvironment. In vitro and in vivo, ACE2 overexpression can suppress proliferation, migration, and invasion of breast cancer cells. Mechanistically, ACE2 inhibits TGF-β1/Smad2 signaling, epithelial-mesenchymal transition (EMT), and other pro-oncogenic pathways. Moreover, ACE2 high expression in breast cancer could enhance anti-tumor immunity and improve response to anti-PD-L1 therapy, exhibiting an increased tumor infiltration of cytotoxic CD8+ T cells. Collectively, ACE2 acts as a tumor suppressor and immune modulator in breast cancer, inhibiting progression via TGF-β1/Smad2 and potentiating immune checkpoint blockade, representing a potential therapeutic target.

Keywords:  Angiotensin-converting enzyme-2; Breast cancer; Immune infiltration; Transforming growth factor-β

DOI:  https://doi.org/10.1016/j.bbadis.2026.168224
NPJ Breast Cancer. 2026 Mar 14.

HIF-1-regulated TPM3 links hypoxia to motility and invasion beyond the hypoxic fraction in triple-negative breast cancer.

Chumin Zhou, Jack T Crusher, Kate Friesen, Sophie A Twigger, Eduard Petrosyan, Graham Booker, Priya Samuel, Eileen E Parkes, Ester M Hammond.

Hypoxia is a defining feature of triple-negative breast cancer (TNBC), driving invasion, metastasis, and therapy resistance. Understanding the molecular effectors of hypoxia is essential to identify new therapeutic targets. Here, we investigated tropomyosin 3 (TPM3), an actin-binding protein that regulates filament stability. TPM3 is significantly upregulated in breast cancer, including in TNBC, where elevated levels correlate with poor overall survival. Using validated hypoxia signatures and TNBC cell models, we show that TPM3 is induced in physiologically relevant hypoxic conditions in a HIF-1-dependent manner. Both mRNA and protein levels of TPM3 increased in response to hypoxia, and TPM3 colocalised with F-actin, supporting cytoskeletal organisation. Functional assays demonstrated that depletion or inhibition of TPM3 impaired cell morphology, motility, and invasion in hypoxic TNBC cells, while not affecting viability. Notably, TPM3 inhibition synergised with Paclitaxel and Doxorubicin, enhancing therapeutic efficacy. In addition, TPM3 was incorporated into extracellular vesicles (EVs), with hypoxia increasing EV-mediated transfer of TPM3 to normoxic cells and promoting their motility. These findings establish TPM3 as a hypoxia-inducible, HIF-1-regulated effector of cytoskeletal dynamics and intercellular communication, underscoring its potential as a therapeutic target to limit TNBC aggressiveness and improve treatment outcomes.

DOI: https://doi.org/10.1038/s41523-026-00927-y
Cell Rep. 2026 Mar 13. pii: S2211-1247(26)00174-9. [Epub ahead of print]45(3): 117096

Radiation-induced autophagy regulates fibroblast mitochondrial metabolism and crosstalk with triple-negative breast cancer cells.

Kevin C Corn, Shannon E Martello, Vinay K Menon, Lucy S Britto, Kara M Simmons, Youssef K Mohamed, Yoanna I Ivanova, Abtin A Ghelmansaraei, Sara A Weidenbach, Tian Zhu, Evan S Krystofiak, Jamey D Young, Vivian Gama, Marjan Rafat.

  Patients with triple-negative breast cancer (TNBC) experience high recurrence rates despite current interventions, which include radiation therapy (RT). Tumor cells thought to be involved in recurrence may survive in part due to their interactions with irradiated fibroblasts following treatment. How fibroblasts metabolically respond to RT and influence the behavior of TNBC cells is poorly understood. In this study, we demonstrate that irradiated fibroblasts undergo dynamic mitochondrial changes that are regulated by autophagy, resulting in a metabolic profile characterized by high levels of mitochondrial respiration and fatty acid oxidation. These metabolic adaptations lead to a secretory profile that induces an aggressive phenotype in TNBC cells that is mitigated when fibroblast autophagy is blocked. Our work reveals a burgeoning link between post-RT metabolic adaptations in fibroblasts and crosstalk with TNBC cells that promotes a microenvironment conducive to recurrence.

Keywords:  CP: cancer; CP: metabolism; autophagy; fatty acid oxidation; fibroblasts; lipid metabolism; mitochondrial elongation; mitochondrial fusion; mitochondrial respiration; radiation therapy; recurrence; triple-negative breast cancer

DOI:  https://doi.org/10.1016/j.celrep.2026.117096
Breast Cancer (Dove Med Press). 2026 ;18 560682

SLAMF8 Promotes M2 Polarization of Macrophages and Enhances Breast Cancer Proliferation.

Jilin Kong, Rui Tian, Shuyan Li, Hongyan Zang, Yan Cheng, Gaofeng Ni, Wenjing Liu, Liguo Gong.

   Background: Breast cancer is characterized by a complex pathogenesis and diverse clinical manifestations. Tumor-associated macrophages (TAMs) play a pivotal role in tumorigenesis, metastasis, and response to anticancer therapies. This study aimed to analyze the functional role of signaling lymphocytic activation molecule family 8 (SLAMF8) in TAMs and its impact on breast cancer cell proliferation.
Methods: The SLAMF8 silencing in THP-1 cells was established by transfection with SLAMF8 shRNA lentiviral particles, and the THP-1 cells were induced to M0 macrophages or M2 macrophages. The M2 macrophage markers, CD11b+CD163, CD206, and IL-10, were measured by flow cytometry and Western blotting. The induced macrophages were cocultured with breast cancer cells (MCF-7 and MDA-MB-231) using a transwell insert. The viability and migration of cancer cells were measured using CCK-8 and transwell migration. The STAT6 and NF-κB pathways were measured using Western blotting. In vivo, mice were co-injected with breast cancer cells and the THP-1-derived macrophages to observe the tumor growth. The NF-κB pathway in tumor tissues was measured by immunohistochemistry and Western blotting.
Results: The SLAMF8 silencing significantly downregulated the number of THP-1-derived M2 macrophages. The viability, migration, and the STAT6 and NF-κB pathways of breast cancer cells were significantly enhanced after co-culture with M2 macrophages compared to co-culture with M0 macrophages. However, the SLAMF8 silencing markedly suppressed the promoting effects of M2 macrophage co-culture on the above factors in cancer cells. In line with the in-vitro results, co-injection with M2 macrophages significantly promoted the tumor growth. Moreover, the SLAMF8 silencing in M2 macrophages downregulated the tumor growth compared with that of cancer cells co-injected with M2 macrophages without SLAMF8 silencing.
Conclusion: This study showed that SLAMF8 silencing downregulated M2 macrophage polarization and weakened the promoting effects of M2 macrophages on breast cancer cells, suggesting a promising therapeutic strategy for breast cancer.

Keywords:  SLAMF8; THP-1 cells; breast cancer; tumor-associated macrophages

DOI:  https://doi.org/10.2147/BCTT.S560682
Naunyn Schmiedebergs Arch Pharmacol. 2026 Mar 20.

Targeting ZNF570 activates ferroptosis to reverse tamoxifen resistance in ER + breast cancer cells.

Yun Ren, Jindan Zhang, Mingting Duan, Ziwei Zhao, Ruqi Guo, Jianzhong Xu, Yanhong Wang, Hongyan Jia.

  The hormone receptors (HR) + /human epidermal growth factor receptor 2 (HER2) - subtype accounts for 60%-70% of primary breast cancer (BC) cases. Tamoxifen (TAM) has been the first-line endocrine therapeutic agent for this subtype for over 30 years and induces clinical responses in more than 70% of estrogen receptor-positive (ER +) tumors. However, 22%-52% of patients develop tumor recurrence or distant metastasis due to acquired tamoxifen resistance, which highlights the critical need to explore resistance mechanisms as well as identify new therapeutic targets for improving patient prognosis. The objective is to examine the role of ZNF570 in tamoxifen resistance of ER + BC. Analyses of The Cancer Genome Atlas (TCGA) database coupled with validation with clinical samples indicated that ZNF570 is overexpressed in HR + BC. Importantly, ZNF570 expression is linked to a poorer patient prognosis and serves as an independent prognostic indicator for HR + BC. Furthermore, ZNF570 expression is significantly higher in tumor tissues from tamoxifen-resistant patients than in those from tamoxifen-sensitive patients. Tamoxifen-resistant cell models (MCF7-TAM and T47D-TAM) were established by continuously exposing MCF-7 and T47D cells to tamoxifen for induction. These models demonstrated that ZNF570 expression is higher in resistant cells than their parental counterparts, and this expression level exhibits a positive link with estrogen receptor alpha (ERα) expression levels. Functional experiments demonstrated that ZNF570 knockout in tamoxifen-resistant cells significantly increased the cells' sensitivity to tamoxifen and reduced ER expression. Conversely, ZNF570 overexpression in parental MCF-7 as well as T47D cells decreased cells' sensitivity to tamoxifen and increased ER expression. Furthermore, ZNF570 was found to promote proliferation, invasion, and migration of ER + BC cells. Tumor-promoting effect of ZNF570 in vivo was validated by nude mouse xenograft experiments. Mechanistically, proteomic analyses and combined in vitro as well as in vivo experiments verified that ZNF570 knockout reverses tamoxifen resistance by activating ferroptosis. This ferroptosis activation is mediated by downregulating the expression of glutathione peroxidase 4 (GPX4) coupled with cystine/glutamate transporter (XCT), upregulating the expression of tumor protein p53 (TP53), rising intracellular levels of reactive oxygen species (ROS), ferrous ions (Fe2⁺), and malondialdehyde (MDA), and decreasing intracellular content of reduced glutathione (GSH). In contrast, ZNF570 overexpression inhibits ferroptosis. In conclusion, ZNF570 promotes tamoxifen resistance in ER + BC cells by enhancing ER activity and suppressing ferroptosis, demonstrating that ZNF570 may act as a promising therapeutic target for reversing tamoxifen resistance in ER + BC.

Keywords:  Estrogen receptor-positive breast cancer; Ferroptosis; Tamoxifen resistance; ZNF570

DOI:  https://doi.org/10.1007/s00210-026-05171-6
NPJ Breast Cancer. 2026 Mar 17.

Androgen receptor localisation and protein interactions provide insight into steroid mediated metabolic shifts in endocrine resistant breast cancer.

Rachel Bleach, Emir Bozkurt, Jingqi Xin, Katherine M Sheehan, Sally Shirran, Stephanie Agbana, Mihaela Ola, Leonie Young, Nicole S Spoelstra, Jennifer K Richer, Ana Cristina Vargas, Leonard D Goldstein, Heloisa H Milloli, Christine L Chaffer, Michael W O'Reilly, Jochen Hm Prehn, Marie McIlroy.

Aromatase inhibitors (AI) are standard therapy for hormone receptor-positive breast cancer in post-menopausal women, yet recurrence remains common. Our previous work suggests that an androgen‑dominated steroid environment may drive AI resistance. Although most androgen research has focused on classical genomic pathways in reproductive tissues, interest is growing in their non‑reproductive functions. In particular, the role of cytoplasmic AR has recently gained attention, and its connection to metabolic modulation remains largely unexplored in the context of breast cancer. Cytoplasmic AR was evaluated in a breast cancer microarray (n = 875), validated in an independent cohort (n = 30), and examined in metastatic biopsies (n = 12). LC‑MS/MS identified AR‑interacting proteins in AI‑resistant cells exposed to adrenal androgens, confirmed by co‑immunoprecipitation and imaging. High cytoplasmic AR predicted poor survival in post‑menopausal patients, especially luminal B cancers (p = 0.0085). AI‑resistant models showed diffuse AR localisation throughout the cytoplasm and nucleus accompanied by increased mitochondrial mass and membrane potential, and elevated oxidative phosphorylation and glycolysis. Label‑free mass spectrometry identified G3BP1, SLIRP and IGFBP5 as AR interactors linked to stress response, metabolic adaptation and ERα repression. The findings of this study highlight the prognostic potential of cytoplasmic AR immunoreactivity in specific breast cancer subtypes and uncover novel cytoplasmic AR protein interactions that may mediate metabolic adaptations during the development of endocrine-resistance.

DOI: https://doi.org/10.1038/s41523-026-00924-1
Oncogene. 2026 Mar 21.

Cancer-associated fibroblasts as key regulators of lipid metabolism in the tumour microenvironment.

Jessamy Adams, Caterina M Suelzu, Gabriele Strusi, Justin Stebbing.

Alterations in metabolism are recognised as a hallmark of cancer, allowing for rapid proliferation in an environment often hypoxic and short of nutrients. Cells within the tumour microenvironment (TME) often undergo metabolic alterations to adapt to these conditions, and this can also contribute to tumour progression. Cancer associated fibroblasts (CAFs) are amongst the most abundant non-cancerous cells in the TME and the main cells responsible for production and maintenance of the extracellular matrix. However, CAF subtypes can impact tumours in different ways and have been shown to play a role in alterations to lipid metabolism within tumours, being able to produce and secrete lipids, internalise them from the surrounding environment, and undergo fatty acid oxidation. Whilst this is still an emerging area of research, it appears that CAFs can have opposing roles in lipid metabolism in different types of cancer. Understanding the different metabolic pathways utilised in both CAFs and cancer cells and how external factors such as obesity and high fat diets influence them, could provide novel treatment avenues in the future. This review explores the literature surrounding lipid metabolism in CAFs and how this influences tumour progression and treatment resistance.

DOI: https://doi.org/10.1038/s41388-026-03733-9