Persistent Activation of NF-κB in BRCA1-Deficient Mammary Progenitors Drives Aberrant Proliferation and Accumulation of DNA Damage.
Persistent Activation of NF-κB in BRCA1-Deficient Mammary Progenitors Drives Aberrant Proliferation and Accumulation of DNA Damage.
复制标题
DOI：
10.1016/j.stem.2016.05.003
复制
发表时间：
2016-07-07
期刊：
影响因子：
23.9
通讯作者：
Pratt MA
中科院分区：
文献类型：
--
作者：
Sau A;Lau R;Cabrita MA;Nolan E;Crooks PA;Visvader JE;Pratt MA
人类 BRCA1 突变携带者和 BRCA1 缺陷小鼠乳腺含有异常的乳腺腔祖细胞群，它们可以以不依赖激素的方式形成 3D 集落。这些假定的乳腺癌前兆的内在细胞调节缺陷尚不清楚。我们发现核因子 kappaB (NF-κB) (p52/RelB) 在 BRCA1 缺陷的乳腺腔祖细胞亚群中持续激活。激素非依赖性管腔祖细胞集落形成需要 NF-κB、共济失调性毛细血管扩张突变 (ATM) 和 kappaB 激酶抑制剂 IKKα。黄体酮 (P4) 刺激的增殖导致 Brca1−/− 小鼠乳腺 DNA 损伤灶显着增强。在体内，NF-κB 抑制阻止了 Brca1−/− 激素依赖性集落形成细胞的恢复。大多数人类 BRCA1mut/+ 乳腺显示核 NF-κB 的小叶显着表达。我们得出的结论是，Brca1−/− 管腔祖细胞的异常增殖能力与复制相关的 DNA 损伤反应有关，其中乳腺祖细胞的增殖是通过损伤诱导的自体 NF-κB 信号传导而得以延续的。 BRCA1 突变会增加患乳腺癌的风险，并与不依赖激素的乳腺腔祖细胞异常增殖有关。在这项研究中，Sau 等人。发现 BRCA1 缺陷的管腔祖细胞中 DNA 损伤诱导的 NF-κB 激活是激素非偶联增殖所需的细胞机制，增加了基因组不稳定和转化的风险。
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-κB) (p52/RelB) is persistently activated in a subset of BRCA1-deficient mammary luminal progenitors. Hormone-independent luminal progenitor colony formation required NF-κB, ataxia telangiectasia-mutated (ATM), and the inhibitor of kappaB kinase, IKKα. Progesterone (P4)-stimulated proliferation resulted in a marked enhancement of DNA damage foci in Brca1−/− mouse mammary. In vivo, NF-κB inhibition prevented recovery of Brca1−/− hormone-independent colony-forming cells. The majority of human BRCA1mut/+ mammary glands showed marked lobular expression of nuclear NF-κB. 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-κB signaling. BRCA1 mutations increase the risk for breast cancer and have been linked with hormone-independent abnormal proliferation of mammary luminal progenitors. In this study, Sau et al. find that DNA-damage-induced NF-κB activation in BRCA1-deficient luminal progenitors is a cellular mechanism required for hormone-uncoupled proliferation, increasing the risk of genomic instability and transformation.
登录
查看更多内容
影响因子：
3.8
作者：
Barham W;Chen L;Tikhomirov O;Onishko H;Gleaves L;Stricker TP;Blackwell TS;Yull FE
通讯作者：
Yull FE
影响因子：
5.3
作者：
Gonzalez-Suarez, Eva;Branstetter, Daniel;Dougall, William C.
通讯作者：
Dougall, William C.
影响因子：
64.8
作者：
KIPLING, D;COOKE, HJ
通讯作者：
COOKE, HJ
影响因子：
4.3
作者：
Lau, Rosanna;Niu, Min Ying;Pratt, M. A. Christine
通讯作者：
Pratt, M. A. Christine
影响因子：
56.9
作者：
Lee, JH;Paull, TT
通讯作者：
Paull, TT