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

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.