Epigenomic disorder and partial EMT impair luminal progenitor integrity in Brca1-associated breast tumorigenesis
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.
Authors
- Marisa M. Faraldo (ORCID: https://orcid.org/0000-0001-9497-1171)
- Aurélie Chiche (ORCID: https://orcid.org/0000-0003-0081-5851)
- Hélène Salmon (ORCID: https://orcid.org/0000-0002-2253-3807)
- Jérémy Mesple (ORCID: https://orcid.org/0000-0003-2537-3463)
- Amandine Trouchet
- Mélissa Saichi (ORCID: https://orcid.org/0000-0001-6461-1482)
- Céline Vallot (ORCID: https://orcid.org/0000-0003-1601-2359)
- Camille Landragin (ORCID: https://orcid.org/0000-0002-9157-1524)
- Renaud Leclère (ORCID: https://orcid.org/0000-0001-8737-6817)
- Marthe Laisné (ORCID: https://orcid.org/0000-0003-1473-047X)
- Kyra J. E. Borgman (ORCID: https://orcid.org/0000-0001-7898-2911)
- Adeline Durand
- Pacôme Prompsy (ORCID: https://orcid.org/0000-0003-4375-7583)
- Anne Vincent-Salomon
Institutions
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Institut Pasteur (FR)
- Université Paris Sciences et Lettres (FR)
- Dynamique de l'information génétique : bases fondamentales et cancer (FR)
- Dynamique du noyau (FR)
- Génétique et biologie du développement (FR)
- École Polytechnique Fédérale de Lausanne (CH)
- Institut Curie (FR)
- University of Lausanne (CH)
Publication Details
- Journal
- Molecular Cancer
- Published
- 2025-04-28
- DOI
- https://doi.org/10.1186/s12943-025-02331-9
- Citations
- 9
- Primary Topic
- Epigenetics and DNA Methylation
- Type
- article
- Field-Weighted Citation Impact
- 7.25
Funders
- Equipex
- Agence Nationale de la Recherche
- Institut National de la Santé et de la Recherche Médicale
- Fondation pour la Recherche Médicale
- Institut National Du Cancer
- Fondation Bettencourt Schueller
- Direction Générale de l’offre de Soins
- Horizon 2020 Framework Programme
- HORIZON EUROPE European Research Council