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<p>In breast cancer related to the <i>BRCA1</i> mutation, luminal progenitor cells are believed to be the cells of origin, yet how these cells transform into invasive cancer cells remain poorly understood. Here, we combine single-cell epigenomic and transcriptomic data to reconstitute sequences of events in luminal cells that lead to tumorigenesis. Upon deletion of <i>Trp53</i> and <i>Brca1</i>, we find that luminal progenitors display an extensive epigenomic disorder associated with a loss of cell identity. These cells then progress to tumor formation through a partial epithelial-to-mesenchymal transition, orchestrated by Snail and the timely activation of immunosuppressive and FGF signaling with their microenvironment. In human samples, pre-tumoral changes can be detected in early stage, basal-like tumors, which rarely recur, as well as in normal-like mammary glands of <i>BRCA1</i> mutation carriers who have had cancer. Our study fills critical gaps in our understanding of <i>BRCA1</i>-driven tumorigenesis, opening perspectives for the early monitoring of individuals with high cancer risk.</p> Graphical Abstract <p></p>

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Epigenomic disorder and partial EMT impair luminal progenitor integrity in Brca1-associated breast tumorigenesis

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年4月28日

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  • Camille Landragin,
  • Melissa Saichi,
  • Marthe Laisné,
  • Adeline Durand,
  • Pacôme Prompsy,
  • Renaud Leclere,
  • Jérémy Mesple,
  • Kyra Borgman,
  • Amandine Trouchet,
  • Marisa M. Faraldo,
  • Aurélie Chiche,
  • Anne Vincent-Salomon,
  • Hélène Salmon,
  • Céline Vallot

摘要

In breast cancer related to the BRCA1 mutation, luminal progenitor cells are believed to be the cells of origin, yet how these cells transform into invasive cancer cells remain poorly understood. Here, we combine single-cell epigenomic and transcriptomic data to reconstitute sequences of events in luminal cells that lead to tumorigenesis. Upon deletion of Trp53 and Brca1, we find that luminal progenitors display an extensive epigenomic disorder associated with a loss of cell identity. These cells then progress to tumor formation through a partial epithelial-to-mesenchymal transition, orchestrated by Snail and the timely activation of immunosuppressive and FGF signaling with their microenvironment. In human samples, pre-tumoral changes can be detected in early stage, basal-like tumors, which rarely recur, as well as in normal-like mammary glands of BRCA1 mutation carriers who have had cancer. Our study fills critical gaps in our understanding of BRCA1-driven tumorigenesis, opening perspectives for the early monitoring of individuals with high cancer risk.

Graphical Abstract