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HER2/EGFR in Cancer Research / Advanced Breast Cancer Therapies · Journal article
Frontiers in Endocrinology · August 12, 2026
Encouraging direction, but not yet definitive.
This mechanistic study demonstrates that adipocyte-derived estrogen reduces TROP2 expression via ERα signaling in ERα-positive breast cancer cell lines and counteracts TROP2-directed antibody–drug conjugate efficacy in vitro. The effect is selective to ERα-positive cancers and is reversed by estrogen pathway inhibition, but the findings are restricted to cultured cells and require in vivo and clinical validation to assess therapeutic relevance.
In vitro mechanistic cell culture study with correlative in silico analyses and patient cohort stratification. ERα-positive breast cancer cell lines MCF-7 and T47D; ERα-negative breast cancer cell line MDA-MB-231; differentiated 3T3-L1 adipocytes; patient tumors from overweight/obese and normal-weight individuals stratified by ERα status.. Intervention: Adipocyte-derived conditioned media; estradiol exposure; TROP2-directed antibody–drug conjugates (Sacituzumab Govitecan and Datopotamab Deruxtecan). Compared with: ERα inhibition (tamoxifen, fulvestrant); estrogen production blockade; control (untreated or vehicle-treated cells); ERα-negative breast cancer models.
Adipocyte conditioned media significantly reduced TROP2 expression at transcript and protein levels selectively in ERα-positive BC models (MCF-7, T47D) Elevated 17β-estradiol levels were detected in adipocyte conditioned media, and estradiol exposure recapitulated TROP2 downregulation ERα inhibition with tamoxifen and fulvestrant, or blockade of estrogen production, abrogated adipocyte-driven TROP2 downregulation
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These findings suggest that obesity-associated adipose tissue dysfunction may contribute to resistance to TROP2-directed ADCs in ERα-positive breast cancer patients via estrogen-mediated suppression of TROP2. If confirmed in vivo and clinically, this could support combining TROP2-directed ADCs with estrogen pathway inhibitors in obese patients with ERα-positive disease, but the evidence remains preliminary and requires clinical validation.
A mechanistic study in cell culture models demonstrating that adipocyte-derived estrogen reduces TROP2 expression and ADC efficacy in ERα-positive breast cancer, supported by correlative in silico and patient cohort data but lacking in vivo validation or clinical outcome evidence.
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These findings suggest that obesity-associated adipose tissue dysfunction may contribute to resistance to TROP2-directed ADCs in ERα-positive breast cancer patients via estrogen-mediated suppression of TROP2. If confirmed in vivo and clinically, this could support combining TROP2-directed ADCs with estrogen pathway inhibitors in obese patients with ERα-positive disease, but the evidence remains preliminary and requires clinical validation.
Graded across the dimensions that decide whether you should act, each from what the source actually supports. There is no single score, and where a dimension was not assessed it says so.
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.
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