bims-merabr 2026-08-30 papers

Front Endocrinol (Lausanne). 2026 ;17 1866290

Adipocyte-derived estrogen signaling influences TROP2 expression in ERα-positive breast cancer.

Luca Gelsomino, Linda Manna, Vittoria Marchio, Piercarlo Del Console, Giuseppina Augimeri, Cinzia Giordano, Balázs Győrffy, Daniela Bonofiglio, Carmine De Angelis, Stefania Catalano, Ines Barone.

Background: Obesity-associated alterations in the tumor microenvironment (TME) modulate breast cancer (BC) progression. In obese individuals, adipocytes, the predominant stromal component of breast tissue, display an altered endocrine and inflammatory profile, leading to increased secretion of hormones, adipokines, and cytokines that influence epithelial cell behavior and contribute to tumor progression and therapeutic resistance. In the metastatic setting, antibody-drug conjugates (ADCs) have expanded the therapeutic landscape of BC. However, resistance remains a clinical challenge, with loss or downregulation of the target antigen representing a key mechanism. Increasing evidence indicates that TME-derived signals regulate therapeutic target expression. Among these, Trophoblast Cell Surface Antigen 2 (TROP2), a clinically validated ADC target, can be modulated by stromal-derived factors Here, we investigated whether adipocytes regulate TROP2 expression and influence the efficacy of TROP2-directed ADCs in BC cells.
Methods: Conditioned media (CM) from differentiated 3T3-L1 adipocytes were applied to ERα-positive (MCF-7, T47D) and ERα-negative (MDA-MB-231) BC cells. TROP2 expression was evaluated by qRT-PCR and immunoblotting. Estradiol levels in adipocyte CM were quantified by ELISA, and ERα signaling was inhibited using tamoxifen and fulvestrant. In silico analyses assessed the relationship between ERα signaling and TACSTD2 expression and evaluated TACSTD2 levels in BC cohorts stratified by body mass index (BMI). Cell viability assays determined responsiveness to Sacituzumab Govitecan and Datopotamab Deruxtecan.
Results: Adipocyte-derived CM significantly reduced TROP2 expression at transcript and protein levels, selectively in ERα-positive BC models. Elevated 17β-estradiol levels were detected in adipocyte CM, and estradiol exposure recapitulated TROP2 downregulation. Pharmacological inhibition of ERα signaling or the blockade of estrogen production abrogated this effect, supporting a role for ERα activation. In silico analyses suggested a functional link between ERα and TROP2. TROP2 expression was reduced in tumors from overweight/obese patients with ERα-positive BC, but not in ERα-negative cases. Functionally, adipocyte CM counteracted the antiproliferative effects of Sacituzumab Govitecan and Datopotamab Deruxtecan in ERα-positive BC cells, an effect that was reversed by ERα inhibition.
Conclusions: These findings identify an estrogen-dependent, adipocyte-driven mechanism that modulates TROP2 expression and reduces responsiveness to TROP2-directed ADCs in ERα-positive BC models. Our data highlight the contribution of obesity-associated adipose tissue dysfunction to variability in targeted therapy response and warrant further investigation in clinically relevant settings.

Keywords: ADCs; TROP2; adipocytes; breast cancer; estrogen receptor alpha; obesity

DOI: https://doi.org/10.3389/fendo.2026.1866290

Int J Mol Sci. 2026 Aug 18. pii: 7382. [Epub ahead of print]27(16):

Loss of TIMM8A Inhibits Breast Cancer Progression Through Promoting HSPA9 Ubiquitination and Degradation via Competitive Interaction with RNF4.

Yi Wu, Rujiao Liu, Jian Zhang, Shuiping Gao.

To investigate the role and underlying mechanisms of TIMM8A in breast cancer progression. The expression of TIMM8A in breast cancer tissues and cell lines was assessed. Functional assays were performed to evaluate the effects of TIMM8A knockdown on proliferation, metastasis, and apoptosis in BT549 and MCF-7 cells. Co-immunoprecipitation (Co-IP) and ubiquitination assays were used to examine the interaction between TIMM8A and HSPA9, as well as the involvement of the E3 ubiquitin ligase RNF4. PI3K/AKT pathway activity was assessed by Western blotting. In vivo tumor growth was evaluated using a xenograft mouse model. TIMM8A was significantly upregulated in breast cancer tissues and cell lines, and high TIMM8A expression correlated with poor prognosis. TIMM8A knockdown suppressed proliferation and metastasis while inducing apoptosis in vitro. Mechanistically, TIMM8A interacted with HSPA9 and maintained its protein stability by inhibiting RNF4-mediated ubiquitination and degradation, thereby sustaining PI3K/AKT signaling activation. Conversely, TIMM8A depletion reduced HSPA9 stability and attenuated the pathway. Rescue experiments confirmed that HSPA9 overexpression restored PI3K/AKT activation and reversed TIMM8A-knockdown-induced malignant suppression. In vivo, TIMM8A silencing efficiently inhibited tumor growth, accompanied by reduced HSPA9 and Ki-67 expression and decreased PI3K/AKT phosphorylation. TIMM8A promotes breast cancer progression through the TIMM8A/HSPA9/PI3K/AKT regulatory axis, highlighting TIMM8A as a promising prognostic biomarker and potential therapeutic target for breast cancer.

Keywords: HSPA9; RNF4; TIMM8A; breast cancer; ubiquitination

DOI: https://doi.org/10.3390/ijms27167382

Adv Sci (Weinh). 2026 Aug 29. e77504

Cancer-Associated Fibroblasts Promote Glucose Metabolic Reprogramming and Progression of Triple-Negative Breast Cancer via Exosomal circFAD104-Mediated Intercellular Communication.

Lei Wang, Xiaoyan Li, Yiran Liang, Yifei Wang, Yuhan Jin, Jianing Wang, Dan Luo, Yuxia Yang, Jingze Yang, Yaming Li, Tong Chen, Dianwen Han, Zekun Wang, Wenjing Zhao, Bing Chen, Lijuan Wang, Qifeng Yang.

Triple-negative breast cancer (TNBC) is characterized by high metastatic tendency and poor prognosis, largely driven by dynamic crosstalk between cancer cells and the tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs) are a major component of the TME, yet their functional contributions to TNBC progression remain incompletely understood. In this study, we isolated exosomes from patient-derived CAFs and normal fibroblasts (NFs), and profiled their circRNA content using RNA sequencing. circFAD104 was significantly enriched in CAFs and their derived exosomes, with elevated stromal expression confirmed by qRT-PCR and in situ hybridization (ISH). PKH26 labeling demonstrated that CAF-derived exosomes efficiently deliver circFAD104 to TNBC cells, where it enhances cancer stemness, metastasis, and glycolysis. Mechanistically, circFAD104 acts as a molecular scaffold to promote the interaction between the E3 ubiquitin ligase MARCHF8 and its substrate PGM1, facilitating MARCHF8-mediated K48-linked ubiquitination and subsequent proteasomal degradation of PGM1. Loss of PGM1 redirects glucose flux from glycogen synthesis toward glycolysis, thereby fueling tumor progression. Clinically, high circFAD104 levels were correlated with poorer overall survival in breast cancer patients. These findings uncover a CAF-exosomal circFAD104 axis that reprograms glucose metabolism to drive TNBC progression via the circFAD104/MARCHF8/PGM1 pathway, highlighting its potential as a stroma-targeted biomarker and prognostic predictor.

Keywords: cancer‐associated fibroblasts; circFAD104; exosome; glycolysis; triple‐negative breast cancer

DOI: https://doi.org/10.1002/advs.77504

Nat Commun. 2026 Jul 24. pii: 9029. [Epub ahead of print]17(1):

Enzymatic activity-independent NANS stabilizes LATS2 to drive growth and therapeutic resistance in HR+/HER2- breast cancer.

Jia-Yang Cai, Min-Ying Huang, Shao-Ying Yang, Fang-Lin Zhang, Yin-Ling Zhang, Lisa Andriani, Qian Zhao, A-Yong Cao, Da-Qiang Li, Zhi-Ming Shao.

Hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+ /HER2-) breast cancer is the most common subtype in females, frequently challenged by resistance to endocrine therapy and CDK4/6 inhibitors. Here we show that N-acetylneuraminate synthase (NANS) is significantly upregulated in female HR+ /HER2- breast cancer patients, inversely correlating with patient prognosis. Functionally, NANS promotes tumor growth and confers resistance to tamoxifen and CDK4/6 inhibitors independently of its canonical enzymatic activity. Mechanistically, NANS recruits ubiquitin-specific protease 7 (USP7) to deubiquitinate and stabilize large tumor suppressor kinase 2 (LATS2), leading to canonical Hippo pathway activation and upregulation of estrogen receptor α and CDK4. Reintroducing LATS2 into NANS-depleted cells partially rescues the impaired growth-promoting and drug-resistant phenotypes in vitro and in vivo. Furthermore, the clinical relevance of the NANS-USP7/LATS2 axis is confirmed in patient-derived female HR+ /HER2- breast cancer samples. Together, our findings unveil an enzymatic activity-independent role for NANS in driving therapy resistance, nominating it as a promising therapeutic target.

DOI: https://doi.org/10.1038/s41467-026-75386-x