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Cell. 2019 Jun 27;178(1):135-151.e19. doi: 10.1016/j.cell.2019.06.002.

Inadequate DNA Damage Repair Promotes Mammary Transdifferentiation, Leading to BRCA1 Breast Cancer.

Author information

1
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Departments of Genetics and Medicine, Harvard Medical School, Boston, MA 02115, USA.
2
Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
3
Informatics IT, Merck & Co., Boston, MA 02115, USA.
4
Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
5
Hubrecht Institute, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands.
6
Department of Medicine, Robert Wood Johnson Medical School, Rutgers, New Brunswick, NJ 08901, USA.
7
Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. Electronic address: zli4@rics.bwh.harvard.edu.
8
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Departments of Genetics and Medicine, Harvard Medical School, Boston, MA 02115, USA. Electronic address: david_livingston@dfci.harvard.edu.

Abstract

Loss of BRCA1 p220 function often results in basal-like breast cancer (BLBC), but the underlying disease mechanism is largely opaque. In mammary epithelial cells (MECs), BRCA1 interacts with multiple proteins, including NUMB and HES1, to form complexes that participate in interstrand crosslink (ICL) DNA repair and MEC differentiation control. Unrepaired ICL damage results in aberrant transdifferentiation to a mesenchymal state of cultured, human basal-like MECs and to a basal/mesenchymal state in primary mouse luminal MECs. Loss of BRCA1, NUMB, or HES1 or chemically induced ICL damage in primary murine luminal MECs results in persistent DNA damage that triggers luminal to basal/mesenchymal transdifferentiation. In vivo single-cell analysis revealed a time-dependent evolution from normal luminal MECs to luminal progenitor-like tumor cells with basal/mesenchymal transdifferentiation during murine BRCA1 BLBC development. Growing DNA damage accompanied this malignant transformation.

KEYWORDS:

BRCA1; CtIP; EMT; HES1; ICL repair; NUMB; breast cancer; cell fate; cisplatin; mouse model; single-cell analysis; transdifferentiation

PMID:
31251913
PMCID:
PMC6716369
[Available on 2020-06-27]
DOI:
10.1016/j.cell.2019.06.002

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