bims-merabr 2025-10-19 papers

Int J Mol Sci. 2025 Oct 03. pii: 9666. [Epub ahead of print]26(19):

When Fat Talks: How Adipose-Derived Extracellular Vesicles Fuel Breast Cancer.

Maria Pia Cavaleri, Tommaso Pusceddu, Lucia Sileo, Luna Ardondi, Ilaria Vitali, Ilenia Pia Cappucci, Laura Basile, Giuseppe Pezzotti, Francesco Fiorica, Letizia Ferroni, Barbara Zavan.

Adipose tissue plays a crucial role in the tumor microenvironment (TME), where its secreted extracellular vesicles (EVs) are involved in the complex signaling between tumor cells and surrounding stromal components. This study aims to unravel the mechanisms through which adipocyte-derived EVs influence breast cancer (BC) progression. Human mesenchymal stem cells (hMSCs) were differentiated into adipocytes following a 21-day induction protocol that led to significant accumulation of lipid droplets within the cells. EVs were isolated from the conditioned medium of both hMSC-derived adipocytes and BC cells. Particle size distribution, morphology, and uptake into the recipient cell were investigated via nanoparticle tracking analysis, transmission electron microscopy, and fluorescence microscopy, respectively. Our results show that BC-derived EVs notably impaired cell viability and modulated the expression of key genes involved in apoptosis resistance within stromal cells. On the other hand, stromal-derived EVs significantly altered tumor cell behavior, indicating a dynamic, bidirectional exchange of bioactive signals. These findings underscore the pivotal role of EV-mediated communication in the tumor-stroma interplay, suggesting that adipocyte-cancer cell EV crosstalk contributes to the remodeling of the TME, potentially facilitating tumor progression.

Keywords: adipocyte; breast cancer cells; exosome; extracellular vesicles

DOI: https://doi.org/10.3390/ijms26199666

Int J Mol Sci. 2025 Oct 04. pii: 9686. [Epub ahead of print]26(19):

Metabolic Regulation of Ferroptosis in Breast Cancer.

Natalija Glibetic, Michael Weichhaus.

Breast cancer, a leading global malignancy, exhibits extensive metabolic reprogramming that drives tumorigenesis, therapy resistance, and survival. Ferroptosis, an iron-dependent regulated cell death mechanism characterized by lipid peroxidation, emerges as a promising therapeutic vulnerability, particularly in aggressive subtypes like triple-negative breast cancer (TNBC). This literature review comprehensively explores the metabolic regulation of ferroptosis in breast cancer cells, focusing on how dysregulated pathways modulate sensitivity or resistance. The review will discuss iron homeostasis, including upregulated transferrin receptor 1 (TFR1), diminished ferroportin, mitochondrial dynamics, and ferritinophagy, which catalyze ROS via Fenton reactions. It will examine glutathione (GSH) metabolism through the GPX4-GSH axis, with subtype-specific reliance on cystine import via xCT or de novo cysteine synthesis. Lipid metabolism will be analyzed as the core battleground, highlighting polyunsaturated fatty acid (PUFA) incorporation by ACSL4 promoting peroxidation, contrasted with monounsaturated fatty acid (MUFA) protection via SCD1, alongside subtype adaptations. Further, the review will address tumor microenvironment influences, such as cysteine supply from cancer-associated fibroblasts and oleic acid from adipocytes. Oncogenic signaling (e.g., RAS, mTOR) and tumor suppressors (e.g., p53) will be evaluated for their roles in resistance or sensitivity. Intersections with glucose metabolism (Warburg effect) and selenium-dependent antioxidants will be explored. Therapeutically, the review will consider targeting these nodes with GPX4 inhibitors or iron overload, synergized with immunotherapy for immunogenic cell death. Future directions will emphasize multi-omics integration and patient-derived organoids to uncover subtype-specific strategies for precision medicine in breast cancer.

Keywords: breast cancer; ferroptosis; glutathione metabolism; iron metabolism; lipid peroxidation

DOI: https://doi.org/10.3390/ijms26199686

Cells. 2025 Sep 23. pii: 1484. [Epub ahead of print]14(19):

The Role of Nesprin-4 in Breast Cancer Migration and Invasion.

Badria Fouad Al-Sammak, Lutfiye Yildiz Ozer, Hend Salah Fayed, Nada Mohamed Kafour, Johan Ericsson, Ayman Al Haj Zen, Henning F Horn.

Cancer metastasis is responsible for most cancer-related deaths. Migration and invasion, key steps in the metastatic cascade, require nuclear pliability to traverse the physical barriers of the extracellular matrix and cell-cell junctions. The nuclear envelope (NE) contains LINC complex proteins, including nesprin-4, which regulate nuclear integrity, stiffness, and cell movement. We report that nesprin-4 expression is generally upregulated in breast cancer samples but is reduced in triple-negative breast cancer (TNBC) samples compared to other subtypes. A nesprin-4 expression analysis in 62 breast cancer cell lines showed that nesprin-4 expression correlates positively with cell lines representing less aggressive tumors, while TNBC cell lines have low or no nesprin-4 expression. To determine the role of nesprin-4, we modulated nesprin-4 expression levels in three breast cancer cell lines: MCF7, T47D (luminal A and nesprin-4-positive), and MDA-MB-231 (TNBC and nesprin-4-negative). We found that nesprin-4 promotes migration and invasion by driving cell polarization. However, we also found that nesprin-4 impedes intravasation into endothelial microvessels. Thus, we propose that nesprin-4 plays a dual role in breast cancer, promoting efficient migration and invasion, but blocking intravasation.

Keywords: LINC complex; breast cancer; intravasation; invasion; migration; nesprin-4

DOI: https://doi.org/10.3390/cells14191484

iScience. 2025 Oct 17. 28(10): 113552

Phosphorylation of plectin by Akt3 promotes triple-negative breast cancer cell invasive migration.

Shixue Zheng, Chloe Chan, John M Asara, Liang Zhang, Gerhard Wiche, Y Rebecca Chin.

Triple-negative breast cancer (TNBC) lacks targeted therapeutics and is aggressive with a poor prognosis. The phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway, frequently deregulated in cancers, plays crucial roles in tumorigenesis and cancer progression. However, the distinct functions of the three Akt isoforms (Akt1, Akt2, Akt3) in these processes are not well understood. Here, we focus on Akt3, the least-studied Akt isoform, which is overexpressed in 28% of TNBC cases and significantly promotes TNBC growth, stemness, and epithelial-mesenchymal transition. Through a genome-wide proteomic screen, we identified plectin, a member of the plakin family, as an Akt3 substrate in TNBC cells. The depletion of plectin potently inhibits TNBC cell migration and invadopodia formation, albeit with mild effects on cell growth. The phosphorylation of plectin at Ser4268 by Akt promotes its colocalization with vimentin and TNBC cell migration. Our findings underscore the importance of Akt3-plectin signaling as a potential TNBC therapeutic target.

Keywords: Biochemistry; Cancer; Proteomics

DOI: https://doi.org/10.1016/j.isci.2025.113552

BMC Cancer. 2025 Oct 13. 25(1): 1556

Transcriptomic profiles of endocrine-resistant breast cancer.

Caroline Schagerholm Stanev, Emmanouil G Sifakis, Linnea Hases, Xinsong Chen, Cecilia Williams, Stephanie Robertson, Johan Hartman.

BACKGROUND: The majority of breast cancer patients have tumors expressing estrogen receptor α (ER) and are treated with adjuvant endocrine therapy. However, nearly one-third relapse, most with retained ER expression.
METHODS: This study investigated patients with ER-positive and human epidermal growth factor receptor 2 (HER2)-negative primary breast cancer. Patients with ER-positive relapses within five years of ongoing endocrine therapy were defined as endocrine-resistant (N = 69). Patients with no disease progression after 10 years were defined as endocrine-sensitive (N = 77). RNA was extracted from archived tumor blocks, followed by gene expression analysis.
RESULTS: Significant differences were observed with higher tumor grades, intrinsic subtype risk scores, and upregulated cell-cycle gene sets in resistant compared to sensitive patients' primary tumors. Metabolism-associated gene sets were upregulated, and estrogen-response gene sets downregulated in resistant patients' relapse compared to primary tumors.
CONCLUSIONS: This study highlights gene sets associated with endocrine resistance and identifies transcriptomic and clinicopathological profiles that may serve as potential prognostic markers for therapy response.

Keywords: Breast cancer; Endocrine resistance; Gene expression

DOI: https://doi.org/10.1186/s12885-025-14826-1

Nat Commun. 2025 Oct 15. 16(1): 9168

Loss of BPTF restores estrogen response and suppresses metastasis of mammary tumors.

Context-specific epigenetic dependencies, shaped by chromatin remodeling can create exploitable vulnerabilities for cancer therapies that are unique to tissue types and cellular identities. Here, we show that loss of BPTF (Bromodomain PHD Finger Transcription Factor), a core component of the NURF (Nucleosome Remodeling Factor) complex, results in the emergence of estrogen-responsive, tamoxifen-sensitive, Estrogen Receptor alpha (ERα) positive mammary tumors without altering cancer cell state and tumor pathology. Elevated ERα levels in BPTFKO mammary tumor cells are linked with decreased TGF-β activity and limited metastatic spread of mammary tumor cells to the lungs. Loss of ERα is sufficient to restore TGF-β activity and the metastatic potential in BPTFKO tumors. These findings highlight a mechanism through which BPTF regulates tumor development and progression in mammary epithelial cells, offering insights into the interplay between chromatin remodeling, estrogen signaling, and their resultant adjuvant therapeutic potential in breast cancer.

DOI: https://doi.org/10.1038/s41467-025-64255-8