Persistent Activation of NF-kappaB in BRCA1-Deficient Mammary Progenitors Drives Aberrant Proliferation and Accumulation of DNA Damage
- Author(s)
- Sau, A; Lau, R; Cabrita, MA; Nolan, E; Crooks, PA; Visvader, JE; Pratt, MA;
- Details
- Publication Year 2016-06-07,Volume 19,Issue #1,Page 52-65
- Journal Title
- Cell Stem Cell
- Publication Type
- Journal Article
- Abstract
- 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-kappaB) (p52/RelB) is persistently activated in a subset of BRCA1-deficient mammary luminal progenitors. Hormone-independent luminal progenitor colony formation required NF-kappaB, ataxia telangiectasia-mutated (ATM), and the inhibitor of kappaB kinase, IKKalpha. Progesterone (P4)-stimulated proliferation resulted in a marked enhancement of DNA damage foci in Brca1-/- mouse mammary. In vivo, NF-kappaB inhibition prevented recovery of Brca1-/- hormone-independent colony-forming cells. The majority of human BRCA1mut/+ mammary glands showed marked lobular expression of nuclear NF-kappaB. 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-kappaB signaling.
- Publisher
- Cell Press
- Research Division(s)
- Stem Cells And Cancer
- PubMed ID
- 27292187
- Publisher's Version
- https://doi.org/10.1016/j.stem.2016.05.003
- NHMRC Grants
- NHMRC/1016701, NHMRC/1037230,
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2016-06-17 03:01:35
Last Modified: 2017-08-24 11:38:14