BRCA1 haploinsufficiency for replication stress suppression in primary cells

Shailja Pathania (), Sangeeta Bade, Morwenna Le Guillou, Karly Burke, Rachel Reed, Christian Bowman-Colin, Ying Su, David T. Ting, Kornelia Polyak, Andrea L. Richardson, Jean Feunteun, Judy E. Garber and David M. Livingston ()
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Shailja Pathania: Harvard Medical School
Sangeeta Bade: Dana-Farber Cancer Institute
Morwenna Le Guillou: Stabilité Génétique et Oncogenèse, Université Paris-Sud, CNRS-UMR8200, Gustave-Roussy
Karly Burke: Harvard Medical School
Rachel Reed: Dana-Farber Cancer Institute
Christian Bowman-Colin: Harvard Medical School
Ying Su: Dana-Farber Cancer Institute
David T. Ting: Harvard Medical School
Kornelia Polyak: Harvard Medical School
Andrea L. Richardson: Dana-Farber Cancer Institute
Jean Feunteun: Stabilité Génétique et Oncogenèse, Université Paris-Sud, CNRS-UMR8200, Gustave-Roussy
Judy E. Garber: Harvard Medical School
David M. Livingston: Harvard Medical School

Nature Communications, 2014, vol. 5, issue 1, 1-15

Abstract: Abstract BRCA1—a breast and ovarian cancer suppressor gene—promotes genome integrity. To study the functionality of BRCA1 in the heterozygous state, we established a collection of primary human BRCA1+/+ and BRCA1mut/+ mammary epithelial cells and fibroblasts. Here we report that all BRCA1mut/+ cells exhibited multiple normal BRCA1 functions, including the support of homologous recombination- type double-strand break repair (HR-DSBR), checkpoint functions, centrosome number control, spindle pole formation, Slug expression and satellite RNA suppression. In contrast, the same cells were defective in stalled replication fork repair and/or suppression of fork collapse, that is, replication stress. These defects were rescued by reconstituting BRCA1mut/+ cells with wt BRCA1. In addition, we observed ‘conditional’ haploinsufficiency for HR-DSBR in BRCA1mut/+ cells in the face of replication stress. Given the importance of replication stress in epithelial cancer development and of an HR defect in breast cancer pathogenesis, both defects are candidate contributors to tumorigenesis in BRCA1-deficient mammary tissue.

Date: 2014
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DOI: 10.1038/ncomms6496

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