生物
基因敲除
乳腺癌
转录因子
癌症研究
下调和上调
祖细胞
基因组不稳定性
基因亚型
抑癌基因
增强子
干细胞
细胞生物学
癌症
癌变
基因
遗传学
DNA损伤
DNA
作者
Niamh E. Buckley,Susan Conlon,Karin Jirström,Elaine W. Kay,Nyree Crawford,Anthony O’Grady,Katherine M. Sheehan,Simon S. Mc Dade,Ching-Wei Wang,Dennis J. McCance,Patrick G. Johnston,Richard D. Kennedy,D. Paul Harkin,Paul B. Mullan
出处
期刊:Cancer Research
[American Association for Cancer Research]
日期:2011-03-01
卷期号:71 (5): 1933-1944
被引量:36
标识
DOI:10.1158/0008-5472.can-10-2717
摘要
Little is known about the origin of basal-like breast cancers, an aggressive disease that is highly similar to BRCA1-mutant breast cancers. p63 family proteins that are structurally related to the p53 suppressor protein are known to function in stem cell regulation and stratified epithelia development in multiple tissues, and p63 expression may be a marker of basal-like breast cancers. Here we report that ΔNp63 isoforms of p63 are transcriptional targets for positive regulation by BRCA1. Our analyses of breast cancer tissue microarrays and BRCA1-modulated breast cancer cell lines do not support earlier reports that p63 is a marker of basal-like or BRCA1 mutant cancers. Nevertheless, we found that BRCA1 interacts with the specific p63 isoform ΔNp63γ along with transcription factor isoforms AP-2α and AP-2γ. BRCA1 required ΔNp63γ and AP-2γ to localize to an intronic enhancer region within the p63 gene to upregulate transcription of the ΔNp63 isoforms. In mammary stem/progenitor cells, siRNA-mediated knockdown of ΔNp63 expression resulted in genomic instability, increased cell proliferation, loss of DNA damage checkpoint control, and impaired growth control. Together, our findings establish that transcriptional upregulation of ΔNp63 proteins is critical for BRCA1 suppressor function and that defects in BRCA1-ΔNp63 signaling are key events in the pathogenesis of basal-like breast cancer.
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