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

Hua Wang; Dongxi Xiang; Ben Liu; Aina He; Helena J Randle; Kelvin Xi Zhang; Anushka Dongre; Norman Sachs; Allison P Clark; Luwei Tao; Qing Chen; Vladimir V Botchkarev Jr; Ying Xie; Ning Dai; Hans Clevers; Zhe Li; David M Livingston

doi:10.1016/j.cell.2019.06.002

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

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

Authors

Hua Wang¹, Dongxi Xiang², Ben Liu¹, Aina He², Helena J Randle¹, Kelvin Xi Zhang³, Anushka Dongre⁴, Norman Sachs⁵, Allison P Clark¹, Luwei Tao², Qing Chen², Vladimir V Botchkarev Jr¹, Ying Xie², Ning Dai⁶, Hans Clevers⁵, Zhe Li⁷, David M Livingston⁸

Affiliations

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: [email protected].
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: [email protected].

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
BRCA1 Protein / genetics*
BRCA1 Protein / metabolism
Breast Neoplasms / chemically induced
Breast Neoplasms / genetics*
Breast Neoplasms / pathology
Cell Differentiation / genetics
Cell Transdifferentiation / genetics*
Cell Transformation, Neoplastic
DNA Damage / genetics*
DNA Repair / genetics*
Disease Models, Animal
Epithelial Cells / metabolism
Female
HEK293 Cells
Humans
MCF-7 Cells
Mammary Glands, Animal / pathology*
Membrane Proteins / metabolism
Mice
Mice, Transgenic
Nerve Tissue Proteins / metabolism
Transcription Factor HES-1 / metabolism
Transfection

Substances

BRCA1 Protein
BRCA1 protein, human
Brca1 protein, mouse
Membrane Proteins
Nerve Tissue Proteins
NUMB protein, human
Transcription Factor HES-1
HES1 protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding