Breast cancer, the most common cancer diagnosed among women worldwide, remains a significant clinical challenge due to its molecular heterogeneity and the development of resistance to conventional therapies. This study investigates the potential of silodosin, an α1A-adrenergic receptor (AR) antagonist, as a novel therapeutic agent in breast cancer, an area where its use has not been previously explored. Through detailed in vitro and in silico analyses, we elucidate the complex molecular mechanisms behind silodosin's antitumor effects. We demonstrate its ability to inhibit cell proliferation, induce apoptosis, reduce migration, and prevent 3D spheroid formation. Importantly, these effects are observed across different breast cancer subtypes. Crucially, our integrated approach reveals that silodosin's mechanism is not solely dependent on α1A-AR blockade. Molecular docking studies strongly suggest that silodosin directly interacts with both isoforms of the estrogen receptor (ERα and ERβ) with high affinity, binding to key residues within the ligand-binding domains of these receptors. This points to a new, dual-targeting mechanism of action. While its known α1A-AR antagonism may contribute to its effects, silodosin could also act as an ER ligand, modulating estrogen-driven pathways essential in breast cancer development. This study provides the first experimental and computational evidence supporting the repurposing of silodosin as a potential multi-targeted therapeutic agent for breast cancer, opening promising new opportunities for patients with limited treatment options and encouraging further preclinical and clinical studies.
Pellegrino et al. (Thu,) studied this question.