CDKN1B inactivation impacts ER signaling and drives resistance to endocrine therapy in breast cancer.

BACKGROUND

Hormone receptor-positive (HR + ), HER2-negative breast cancer comprises ~70% of all breast cancer cases and is primarily treated with endocrine therapies such as tamoxifen, aromatase inhibitors, fulvestrant, and CDK4/6 inhibitors. However, resistance arises in ~40% of patients, limiting therapeutic efficacy.

METHOD: We performed integrated genomic, transcriptomic, and functional analyses of 186 HR + /HER2-tumors (88 sensitive, 98 resistant), to identify key drivers of endocrine hormone therapy resistance, Findings were validated functionally using in-vitro and in-vivo models.

RESULTS

We identify frequent CDKN1B (p27) loss-of-function mutations or deletions as a key and clinically actionable driver of endocrine resistance. CDKN1B knockdown in cell lines induces resistance to tamoxifen and fulvestrant, while its restoration re-sensitizes resistant cells. Importantly, CDKN1B-deficient tumors remain responsive to CDK4/6 inhibition, in vitro and in vivo. Immunohistochemistry and transcriptomic analysis of clinical cohorts (n = 138) and TCGA-METABRIC data (n = 1398) identify low p27 as an independent predictor of early relapse and poor survival.

CONCLUSION

Our results highlight CDKN1B as a prognostic biomarker to guide CDK4/6-targeted therapy and a predictor of endocrine resistance in HR + /HER2- breast cancer.