bims-merabr 2025-12-07 papers

bioRxiv. 2025 Nov 21. pii: 2025.11.20.689560. [Epub ahead of print]

Progesterone receptors drive advanced breast cancer phenotypes including circulating tumor-and stem-like cell expansion in the context of ESR1 mutation.

Thu H Truong, Noelle E Gillis, Amy R Dwyer, Rosemary J Huggins, Kyla M Hagen, Sai Harshita Posani, Nuri A Temiz, Carlos Perez Kerkvliet, Ellie M Piepgras, Julie H Ostrander, Geoffrey L Greene, Carol A Lange.

Endocrine therapy resistance remains a major challenge in the treatment of advanced estrogen receptor positive (ER+) breast cancer. This can be driven by acquired mutations in the estrogen receptor gene ( ESR1 ), such as Y537S or D538G, that primarily emerge in patients with prior aromatase inhibitor therapy and results in constitutive estrogen-independent ER activity. Progesterone receptors (PR) are important modifiers of ER activity, in part via direct binding. We previously showed that PR mediates expansion of cancer stem-like cell (CSC) populations and promotes tamoxifen resistance in nuclear ER/PR transcriptional complexes. In this study, we sought to define whether PR function changes in the context of ESR1 mutations. PR readily interacted with wild type (WT), but not Y537S or D538G ERs. RNA-seq and ChIP-seq studies demonstrated that ER+ breast cancer models expressing Y537S ER exhibited a distinct response to progesterone. CSC populations were enhanced in Y537S ER+ cells compared to WT ER+ cells. PR knockdown demonstrated that this property required PR expression but was unresponsive to antiprogestins. Moreover, we identified PR-dependent transcriptional programs such as the unfolded protein response (UPR) that can be leveraged to target CSC populations in Y537S ESR1 -mutant breast cancer. The UPR activator ErSO, but not UPR inhibitors, blocked expansion of CSCs in WT as well as Y537S ER + models. Together, our findings demonstrate a critical interplay between PR and mutant ER function and provide insight into PR-driven pathways including hyperactivation of the stress-sensing UPR that can be exploited as potential therapeutic avenues in advanced ER+ breast cancer.

DOI: https://doi.org/10.1101/2025.11.20.689560

Mol Biol Rep. 2025 Dec 01. 53(1): 145

The interplay between extracellular matrix remodeling and cellular lipid metabolic reprogramming in cancer: a review.

Minyue Yin, Xue Li, Shutian Zhang, Si-An Xie.

Tumor-associated extracellular matrix (ECM) remodeling provides a supportive microenvironment for aberrant cellular behaviors and fate, resulting in tumor progression. Concurrently, reprogrammed lipid metabolism, characterized by dysregulated de novo lipogenesis, fatty acid oxidation (FAO), and lipid peroxidation, serves as a metabolic hallmark of cancer. Emerging evidence reveals a bidirectional crosstalk between ECM remodeling and lipid metabolic rewiring, which collectively drive tumorigenesis, survival, metastasis, and drug resistance. However, the mechanistic links connecting ECM dynamics to cellular lipid metabolism remain incompletely elucidated. In this review, we dissect the mechanistic underpinnings of ECM-lipid metabolism crosstalk, focusing on biochemical and biophysical modulation. In general, ECM-lipid metabolism axis form a self-amplifying feedback circuit, wherein ECM remodeling regulates lipid anabolism and catabolism to fuel energy production, membrane biosynthesis, and signaling molecules generation, while lipid metabolites reciprocally promote ECM degradation or deposition. Targeting critical nodes within this circuit-such as ECM-derived cues (e.g., collagen) or intracellular lipid metabolism pathway (e.g., FAO)-represents a promising strategy to disrupt tumor-stroma coevolution and enhance therapeutic efficacy. Notably, this crosstalk is not static but highly dynamic, exhibiting context-dependent dual roles influenced by variables such as cell state, cancer type, tumor site, and disease stage.

Keywords: Biochemical signaling; Biophysical signaling; Extracellular matrix remodeling; Lipid metabolic reprogramming; Mechanical-metabolic axis

DOI: https://doi.org/10.1007/s11033-025-11283-8

Nat Rev Endocrinol. 2025 Dec 02.

Oestrogen changes at menopause: insights into obesity-associated breast risk and outcomes.

Maiko Sho, Rehana Qureshi, Joyce Slingerland.

Many diseases, including breast cancer, increase in women after menopause and with obesity. This Review addresses novel insights that link obesity, oestrogens, inflammation and breast cancer. Adipose tissue is chronically inflamed in obesity owing to pre-adipocyte expansion and activation of nuclear factor-κB (NF-κB), which upregulate pro-inflammatory cytokines. Obesity also impairs immunosurveillance. Emerging data indicate that the major oestrogens before and after menopause have opposing effects on inflammation. In contrast to the anti-inflammatory properties of premenopausal 17β-oestradiol, the dominant postmenopausal oestrogen, oestrone, is pro-inflammatory. Oestrone is synthesized in adipocytes, therefore the expanded adipose tissue biomass in obesity increases oestrone levels in both men and women, promoting NF-κB-driven inflammation. These pro-inflammatory effects of oestrone are also oncogenic, promoting breast cancer progression in laboratory models. The dominance of oestrone and loss of 17β-oestradiol might underlie the increased prevalence of hormone-responsive breast cancer after menopause, particularly in the context of obesity. Although oestrogens account for much of the excess breast cancer risk with obesity, data on 17β-oestradiol and oestrone levels in the breast and circulation in postmenopausal women, whether or not obesity is present, are limited. Weight loss is associated with reduced breast cancer risk and improved outcomes. The opportunity to use potent weight loss drugs as adjuncts to cancer therapy is discussed.

DOI: https://doi.org/10.1038/s41574-025-01208-7