Berberine overcomes paclitaxel resistance in triple-negative breast cancer by inhibiting HSP90-mediated BRCA1 phosphorylation

Abstract

Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer, and chemotherapy remains a major component of the standard therapy. Although there is an initial response, the tumor will inevitably develop resistance to paclitaxel (PTX) treatment. Berberine (BBR) exhibits excellent anti-cancer activity in a variety of tumor cells and drug-resistant tumor cells. In the in vitro experiments of the study, the effect of BBR on PTX resistance was explored through proliferation assay, flow cytometry. The effects of combined treatment of BBR and PTX on DNA damage in TNBC cells were evaluated by colony formation assay, comet assay and γ-H2AX staining. Western blot and immunofluorescence revealed that HSP90 was highly expressed in the tolerant strain. BBR promotes the ubiquitination and degradation of HSP90 through the ubiquitin-protease system, further inhibits the expression of its client protein p-BRCA1 and improves the sensitivity of PTX treatment. Cell lines overexpressing hsp90 were constructed and it was found that Hsp90 could reverse the sensitivity of BBR to PTX. In addition, a model of transplanted tumors in nude mice was constructed to further verify the regulatory effect of BBR on PTX resistance in TNBC. Collectively, our findings demonstrate that BBR targets HSP90 to activate p-BRCA1-mediated DNA damage, thereby sensitizing non-BRCA-mutated TNBC to PTX. These results suggest HSP90 inhibition as a therapeutic strategy to circumvent chemotherapy resistance and a potential biomarker for predicting TNBC treatment response.

Keywords: Berberine (BBR); DNA damage; HSP90; Paclitaxel resistance; Triple-negative breast cancer (TNBC).