Scholarlink

<p>Long-term survival in breast cancer is often limited by metastatic recurrence arising from disseminated cancer cells that persist in a dormant state. The mechanisms that enable these dormant cells to survive and subsequently reawaken remain incompletely understood. Here an unbiased genome-scale genetic screen identified <i>Med4</i> as a cancer cell-intrinsic gatekeeper in metastatic reactivation. Correspondingly, <i>MED4</i> haploinsufficiency was found to be prevalent in metastatic breast cancer and associated with poorer clinical outcomes. Syngeneic mouse metastasis models revealed that MED4 enforces metastatic dormancy. Mechanistically, and unexpectedly given the canonical role of the Mediator complex in transcriptional activation, MED4 suppresses enhancer priming (H3K4me1) and activation (H3K27ac). Loss of a single <i>Med4</i> allele disrupts enhancer poise, leading to extracellular matrix remodelling and integrin-mediated mechanotransduction programmes that ultimately drive metastatic outgrowth. Together, these findings establish MED4 as a key regulator of breast cancer cell dormancy and nominate <i>MED4</i> haploinsufficiency as a potential predictive biomarker for patients at high risk of metastatic relapse.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Mediator subunit MED4 enforces metastatic dormancy in breast cancer

  • 期刊论文

  • 发表日期：

    2026年6月22日

查看全文
  • Seongyeon S. Bae,
  • Hsiang-Hsi Ling,
  • Jiankang Zhang,
  • Yi Chen,
  • Hong Chen,
  • Dhiraj Kumar,
  • Ajay K. Saw,
  • Kunal Rai,
  • Aaron D. Viny,
  • Ronald A. DePinho,
  • Filippo G. Giancotti

摘要

Long-term survival in breast cancer is often limited by metastatic recurrence arising from disseminated cancer cells that persist in a dormant state. The mechanisms that enable these dormant cells to survive and subsequently reawaken remain incompletely understood. Here an unbiased genome-scale genetic screen identified Med4 as a cancer cell-intrinsic gatekeeper in metastatic reactivation. Correspondingly, MED4 haploinsufficiency was found to be prevalent in metastatic breast cancer and associated with poorer clinical outcomes. Syngeneic mouse metastasis models revealed that MED4 enforces metastatic dormancy. Mechanistically, and unexpectedly given the canonical role of the Mediator complex in transcriptional activation, MED4 suppresses enhancer priming (H3K4me1) and activation (H3K27ac). Loss of a single Med4 allele disrupts enhancer poise, leading to extracellular matrix remodelling and integrin-mediated mechanotransduction programmes that ultimately drive metastatic outgrowth. Together, these findings establish MED4 as a key regulator of breast cancer cell dormancy and nominate MED4 haploinsufficiency as a potential predictive biomarker for patients at high risk of metastatic relapse.