Estrogen receptor α confers Nab-paclitaxel resistance in breast cancer by promoting miR199a-5p maturation to inhibit Caveolin 1 translation

Background Estrogen receptor positive (ER+) breast cancer patients are poorly responsive to Nab-paclitaxel compared to ER negative (ER-) breast cancer patients. Herein, we conducted an investigation regarding the mechanism for ERα confers Nab-paclitaxel resistance in breast cancer.Methods Retrospectively reviewed 116 cases of breast cancer treated with nab-paclitaxel between Jan 2008 and May 2022 in Sir Run Run Shaw Hospital. StataSE 16 software was used to analyze the basic conditions and therapeutic effects. Protein-RNA interactions were validated through RNA immunoprecipitation and RNA pull-down assays. In vitro and in vivo experiments were carried out to testify the effect of ERα on Nab-paclitaxel resistance.Results We show that ERα limits the efficacy of nab-paclitaxel in breast cancer while genetic or pharmacological inhibition of ERα has a synergistic effect with Nab-paclitaxel. Meanwhile, CAV1 expression is negatively correlated to ERα and relevant to the better clinical benefits of Nab-paclitaxel treatment. Importantly, ERα stimulates miR199a-5p maturation to antagonize m6A modification of CAV1 mRNA, thus inhibiting its translation.Conclusions Our results define a novel role of ERα miR199a-5p/CAV1 axis responsible for nab-paclitaxel resistance and propose combining ER antagonist with nab-paclitaxel as a perspective strategy for ER + breast cancer patients.