Non-Canonical Modulation of Vitamin D Receptor Signaling by Paclitaxel in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is characterized by a highly aggressive phenotype and limited therapeutic options. This study investigated whether the vitamin D receptor (VDR) modulates aggressiveness and chemotherapeutic response in TNBC and explored its interaction with paclitaxel (PTX) in the presence of a non-hypercalcemic vitamin D analogue (UVB1). Functional cellular assays, orthotopic murine models, and computational approaches were integrated using murine 4T1 and human MDA-MB-468 TNBC cells with differential VDR expression, including PTX-resistant models. The results show that VDR overexpression reduced invasive capacities in vitro and pulmonary metastatic dissemination in vivo, and sensitized cells to PTX alone or combined with UVB1. 4T1-PTX-resistant cells exhibited elevated VDR levels and less aggressive features compared with wild-type cells. Computational analyses revealed stable PTX binding to an allosteric site near the activation function-2 domain of VDR, further stabilized by UVB1. Functional assays demonstrated that the combination of PTX and UVB1 enhanced the transcriptional activity of VDR compared with UVB1 treatment alone. These findings identify VDR signaling as a modulator of tumor aggressiveness and PTX response in TNBC and support a model in which PTX contributes to nuclear receptor regulation, thus highlighting the relevance of non-canonical drug-receptor interactions in shaping cellular responses to chemotherapy.