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

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.

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. 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.