| First Author | Sau A | Year | 2016 |
| Journal | Cell Stem Cell | Volume | 19 |
| Issue | 1 | Pages | 52-65 |
| PubMed ID | 27292187 | Mgi Jnum | J:238241 |
| Mgi Id | MGI:5818641 | Doi | 10.1016/j.stem.2016.05.003 |
| Citation | Sau A, et al. (2016) Persistent Activation of NF-kappaB in BRCA1-Deficient Mammary Progenitors Drives Aberrant Proliferation and Accumulation of DNA Damage. Cell Stem Cell 19(1):52-65 |
| abstractText | 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 BRCA1(mut/+) 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. |
