Differential Modulation of Galectin-3 by Tamoxifen and Progesterone Receptor Modulators: An In Vitro and In Silico Study

Background/Aim: Tamoxifen remains one of the most widely used endocrine treatments for hormone-receptor-positive breast cancer. However, its partial estrogen-agonist activity in the endometrium is associated with endometrial proliferation, hyperplasia, polyps, and, rarely, carcinoma. Antiprogestins and selective progesterone receptor modulators, including mifepristone and ulipristal acetate, have been proposed as alternative or adjunctive endocrine strategies, but their effects on endometrial molecular remodeling remain insufficiently characterized. This study investigates whether Galectin-3, a multifunctional lectin that is involved in epithelial integrity, angiogenesis, receptor signaling, and tumor-associated remodeling, could serve as a candidate marker of the endometrial epithelial response to endocrine modulation. Materials and Methods: Ishikawa endometrial adenocarcinoma cells were exposed to different concentrations of tamoxifen, mifepristone, and ulipristal acetate. Galectin-3 protein expression was evaluated using Western blot analysis, and densitometric measurements were normalized to β-actin. Complementary STRING and STITCH bioinformatics analyses were performed to examine the molecular interactions linking Galectin-3 with steroid receptor and growth-factor-associated signaling pathways. Results: Tamoxifen produced a biphasic response, characterized by modest induction of Galectin-3 expression at low concentration and marked suppression at intermediate and high concentrations. Mifepristone preserved Galectin-3 expression at low and intermediate concentrations but reduced its expression at the highest concentration. Ulipristal acetate increased Galectin-3 expression at low-to-intermediate concentrations, followed by a return toward baseline at high concentration. STRING and STITCH analyses indicated that Galectin-3 is indirectly linked to steroid receptor signaling through growth-factor-associated pathways, particularly EGFR/ERBB- and VEGF-related networks. Conclusion: Galectin-3 expression differs according to the type and concentration of endocrine modulator used, suggesting that it may reflect distinct endometrial epithelial responses to hormonal treatment. Galectin-3 therefore warrants further investigation as a potential biomarker for assessing endometrial safety during endocrine therapy.