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Background <p>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.</p> Method <p>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.</p> Results <p>We identify frequent <i>CDKN1B</i> (p27) loss-of-function mutations or deletions as a key and clinically actionable driver of endocrine resistance. <i>CDKN1B</i> knockdown in cell lines induces resistance to tamoxifen and fulvestrant, while its restoration re-sensitizes resistant cells. Importantly, <i>CDKN1B</i>-deficient tumors remain responsive to CDK4/6 inhibition, in vitro and in vivo. Immunohistochemistry and transcriptomic analysis of clinical cohorts (<i>n</i> = 138) and TCGA-METABRIC data (<i>n</i> = 1398) identify low p27 as an independent predictor of early relapse and poor survival.</p> Conclusion <p>Our results highlight <i>CDKN1B</i> as a prognostic biomarker to guide CDK4/6-targeted therapy and a predictor of endocrine resistance in HR + /HER2− breast cancer.</p>

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

  • 期刊论文

  • 发表日期：

    2026年4月22日

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  • Suhail Ahmad,
  • Ashwin Butle,
  • Akshay Karn,
  • Roma Sunder,
  • Rohit Mishra,
  • Bhargavi Bawaskar,
  • Pallavi Parab,
  • Vividh Raje,
  • Rohan Chaubal,
  • Tanuja Shet,
  • Gopal Kundu,
  • Sudeep Gupta,
  • Amit Dutt

摘要

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.