Targeting CDK7 reverses tamoxifen resistance through regulating stemness in ER+ breast cancer

Abstract

Background: Although tamoxifen is the mainstay endocrine therapy for estrogen receptor-positive (ER+) breast cancer patients, the emergence of tamoxifen resistance is still the major challenge that results in treatment failure. Tamoxifen is very effective in halting breast cancer cell proliferation; nonetheless, the ability of tamoxifen to target cancer stem and progenitor cell populations (CSCs), a major key player for the emergence of tamoxifen resistance, has not been adequately investigated yet. Thus, we explored whether targeting CDK7 modulates CSCs subpopulation and tamoxifen resistance in ER+ breast cancer cells.

Methods: Mammosphere-formation assay, stem cell biomarkers and tamoxifen sensitivity were analyzed in MCF7 tamoxifen-sensitive cell line and its resistant counterpart, LCC2, following CDK7 targeting by THZ1 or siRNA.

Results: Analysis of clinically relevant data indicated that expression of stemness factor, SOX2, was positively correlated with CDK7 expression in tamoxifen-treated patients. Moreover, overexpression of the stemness gene, SOX2, was associated with shorter overall survival in those patients. Importantly, the number of CSC populations and the expression of CDK7, P-Ser118-ER-α and c-MYC were significantly higher in LCC2 cells compared with parental MCF-7 cells. Moreover, targeting CDK7 inhibited mammosphere formation, CSC-regulating genes, and CSC biomarkers expression in MCF-7 and LCC2 cells.

Conclusion: Our data indicate, for the first time, that CDK7-targeted therapy in ER+ breast cancer ameliorates tamoxifen resistance, at least in part, by inhibiting cancer stemness. Thus, targeting CDK7 might represent a potential approach for relieving tamoxifen resistance in ER+ breast cancer.

Keywords: Breast cancer; Cancer stem cells; Cyclin-dependent kinase; SOX2; Tamoxifen.