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<p>Estrogen receptor-positive breast cancer remains a leading cause of cancer-related death in women, with mortality largely driven by late recurrence of treatment-resistant disease. Loss of MLH1 promotes resistance to estrogen-targeting therapies by uncoupling cell cycle progression from estrogen regulation. Here, we show that even when MLH1 is abundantly expressed, aberrant cytoplasmic localization in a subset of tumor cells drives endocrine therapy resistance by enabling estrogen-independent growth. This resistance arises from failure to undergo robust cell cycle arrest in response to endocrine therapy, creating acute dependency on CDK4/6 activity. Consequently, CDK4/6 inhibitors induce strong regression in cells with cytoplasmic MLH1 compared to cells with nuclear MLH1. As cytoplasmic localization occurs in ~11% of ER+ patients, it represents a contributor to MLH1 dysregulation. Incorporating cytoplasmic MLH1 localization into diagnostics could guide the use of CDK4/6 inhibitors in this hard-to-treat subset.</p>

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Aberrant cytoplasmic localization of MLH1 characterizes a cell population that seeds breast cancer recurrence

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月10日

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  • Aloran Mazumder,
  • Jerry Dewitt,
  • Elena Oropeza,
  • Nindo Punturi,
  • Daniel Lozano,
  • Megha Raghunathan,
  • Jonathan Piscitelli,
  • Elham Sajjadi,
  • Elena GueriniRocco,
  • Konstantinos Venetis,
  • Mariia Ivanova,
  • Eltjona Mane,
  • Marianna Dercole,
  • Alberto Concardi,
  • Nicola Fusco,
  • Carol Manhart,
  • Matthew Bainbridge,
  • Svasti Haricharan

摘要

Estrogen receptor-positive breast cancer remains a leading cause of cancer-related death in women, with mortality largely driven by late recurrence of treatment-resistant disease. Loss of MLH1 promotes resistance to estrogen-targeting therapies by uncoupling cell cycle progression from estrogen regulation. Here, we show that even when MLH1 is abundantly expressed, aberrant cytoplasmic localization in a subset of tumor cells drives endocrine therapy resistance by enabling estrogen-independent growth. This resistance arises from failure to undergo robust cell cycle arrest in response to endocrine therapy, creating acute dependency on CDK4/6 activity. Consequently, CDK4/6 inhibitors induce strong regression in cells with cytoplasmic MLH1 compared to cells with nuclear MLH1. As cytoplasmic localization occurs in ~11% of ER+ patients, it represents a contributor to MLH1 dysregulation. Incorporating cytoplasmic MLH1 localization into diagnostics could guide the use of CDK4/6 inhibitors in this hard-to-treat subset.