The Delta Np63 Proteins Are Key Allies of BRCA1 in the Prevention of Basal-Like Breast Cancer

Niamh Buckley, Susan Conlon, Karin Jirstrom, Elaine W. Kay, Nyree Crawford, Anthony O'Grady, Katherine Sheehan, Simon McDade, Ching-Wei Wang, Dennis McCance, Patrick Johnston, Richard Kennedy, Paul Harkin, Paul Mullan

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

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 Delta Np63 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 Delta Np63 gamma along with transcription factor isoforms AP-2 alpha and AP-2 gamma. BRCA1 required Delta Np63 gamma and AP-2 gamma to localize to an intronic enhancer region within the p63 gene to upregulate transcription of the Delta Np63 isoforms. In mammary stem/progenitor cells, siRNA- mediated knockdown of Delta Np63 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 Delta Np63 proteins is critical for BRCA1 suppressor function and that defects in BRCA1-Delta Np63 signaling are key events in the pathogenesis of basal-like breast cancer. Cancer Res; 71( 5); 1933-44. (c) 2011 AACR.
Original languageEnglish
Pages (from-to)1933-1944
Number of pages12
JournalCancer Research
Volume71
Issue number5
DOIs
Publication statusPublished - 01 Mar 2011

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Fingerprint Dive into the research topics of 'The Delta Np63 Proteins Are Key Allies of BRCA1 in the Prevention of Basal-Like Breast Cancer'. Together they form a unique fingerprint.

Cite this