title: The DeltaNp63 proteins are key allies of BRCA1 in the prevention of basal-like breast cancer.
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 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.
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, United Kingdom.
authors.forename: Niamh E
authors.initials: NE
authors.lastname: Buckley
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Conlon
authors.forename: Karin
authors.initials: K
authors.lastname: Jirstrom
authors.forename: Elaine W
authors.initials: EW
authors.lastname: Kay
authors.forename: Nyree T
authors.initials: NT
authors.lastname: Crawford
authors.forename: Anthony
authors.initials: A
authors.lastname: O'Grady
authors.forename: Katherine
authors.initials: K
authors.lastname: Sheehan
authors.forename: Simon S
authors.initials: SS
authors.lastname: Mc Dade
authors.forename: Ching-Wei
authors.initials: CW
authors.lastname: Wang
authors.forename: Dennis J
authors.initials: DJ
authors.lastname: McCance
authors.forename: Patrick G
authors.initials: PG
authors.lastname: Johnston
authors.forename: Richard D
authors.initials: RD
authors.lastname: Kennedy
authors.forename: D Paul
authors.initials: DP
authors.lastname: Harkin
authors.forename: Paul B
authors.initials: PB
authors.lastname: Mullan
mesh_terms: D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D047369:Chromatin Immunoprecipitation; D005260:Female; D005455:Fluorescent Antibody Technique; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D020033:Protein Isoforms / Q000096:biosynthesis / Q000235:genetics; D034741:RNA, Small Interfering; D020133:Reverse Transcriptase Polymerase Chain Reaction; D046888:Tissue Array Analysis; D015534:Trans-Activators / Q000096:biosynthesis / Q000235:genetics*; D014157:Transcription Factors; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000235:genetics*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
chemical_list: D020033:Protein Isoforms; D034741:RNA, Small Interfering; C115051:TP63 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C111164:BRAP protein, human; D044767:Ubiquitin-Protein Ligases