Journal
CELL STEM CELL
Volume 19, Issue 1, Pages 52-65Publisher
CELL PRESS
DOI: 10.1016/j.stem.2016.05.003
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Funding
- Canadian Breast Cancer Foundation (Ontario)
- Victorian Government
- Australian National Health and Medical Research Council (NHMRC) [1016701]
- NHMRC IRIISS
- Victorian State Government OIS
- National Breast Cancer Foundation [NC-13-32]
- NIH National Cancer Institute [R01 CA158275]
- NIH National Institute of General Medical Sciences [P20GM109005]
- Cancer Council Victoria Scholarship
- Cancer Therapeutics CRC Top-Up Scholarship
- NHMRC Australia Fellowship [1037230]
- National Breast Cancer Foundation [NC-13-32] Funding Source: researchfish
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Human BRCA1 mutation carriers and BRCA1-deficient mouse mammary glands contain an abnormal population of mammary luminal progenitors that can form 3D colonies in a hormone-independent manner. The intrinsic cellular regulatory defect in these presumptive breast cancer precursors is not known. We have discovered that nuclear factor kappaB (NF-kappa B) (p52/RelB) is persistently activated in a subset of BRCA1-deficient mammary luminal progenitors. Hormone-independent luminal progenitor colony formation required NF-kappa B, ataxia telangiectasia-mutated (ATM), and the inhibitor of kappaB kinase, IKK alpha. Progesterone (P4)-stimulated proliferation resulted in a marked enhancement of DNA damage foci in Brca1(-/-) mouse mammary. In vivo, NF-kappa B inhibition prevented recovery of Brca1(-/-) hormone-independent colony-forming cells. The majority of human BRCA1(mut/+) mammary glands showed marked lobular expression of nuclear NF-kappa B. We conclude that the aberrant proliferative capacity of Brca1(-/-) luminal progenitor cells is linked to the replication-associated DNA damage response, where proliferation of mammary progenitors is perpetuated by damage-induced, autologous NF-kappa B signaling.
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