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

Hdl Handle:
http://hdl.handle.net/10147/126088
Title:
The {Delta}Np63 Proteins Are Key Allies of BRCA1 in the Prevention of Basal-Like Breast Cancer.
Authors:
Buckley, Niamh E; Conlon, Susan J; Jirstrom, Karin; Kay, Elaine W; Crawford, Nyree T; O'Grady, Anthony; Sheehan, Katherine; Mc Dade, Simon S; Wang, Ching-Wei; McCance, Dennis J; Johnston, Patrick G; Kennedy, Richard D; Harkin, D Paul; Mullan, Paul B
Affiliation:
Authors' Affiliations: Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, United Kingdom; Department of Surgery, Beaumont Hospital and Royal College of Surgeons in Ireland, Dublin, Ireland; Center for Molecular Pathology, Department of Laboratory Medicine, Malmö University Hospital, Lund University, Malmö, Sweden; and National Taiwan University of Science and Technology, Graduate institute of Bioengineering, Taipei, Taiwan.
Citation:
The {Delta}Np63 Proteins Are Key Allies of BRCA1 in the Prevention of Basal-Like Breast Cancer. 2011, 71 (5):1933-44 Cancer Res.
Journal:
Cancer research
Issue Date:
1-Mar-2011
URI:
http://hdl.handle.net/10147/126088
DOI:
10.1158/0008-5472.CAN-10-2717
PubMed ID:
21363924
Additional Links:
http://cancerres.aacrjournals.org/content/71/5/1933.long
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. Cancer Res; 71(5); 1933-44. ©2011 AACR.
Item Type:
Article
Language:
en
ISSN:
1538-7445

Full metadata record

DC FieldValue Language
dc.contributor.authorBuckley, Niamh Een
dc.contributor.authorConlon, Susan Jen
dc.contributor.authorJirstrom, Karinen
dc.contributor.authorKay, Elaine Wen
dc.contributor.authorCrawford, Nyree Ten
dc.contributor.authorO'Grady, Anthonyen
dc.contributor.authorSheehan, Katherineen
dc.contributor.authorMc Dade, Simon Sen
dc.contributor.authorWang, Ching-Weien
dc.contributor.authorMcCance, Dennis Jen
dc.contributor.authorJohnston, Patrick Gen
dc.contributor.authorKennedy, Richard Den
dc.contributor.authorHarkin, D Paulen
dc.contributor.authorMullan, Paul Ben
dc.date.accessioned2011-03-29T13:37:06Z-
dc.date.available2011-03-29T13:37:06Z-
dc.date.issued2011-03-01-
dc.identifier.citationThe {Delta}Np63 Proteins Are Key Allies of BRCA1 in the Prevention of Basal-Like Breast Cancer. 2011, 71 (5):1933-44 Cancer Res.en
dc.identifier.issn1538-7445-
dc.identifier.pmid21363924-
dc.identifier.doi10.1158/0008-5472.CAN-10-2717-
dc.identifier.urihttp://hdl.handle.net/10147/126088-
dc.description.abstractLittle 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. Cancer Res; 71(5); 1933-44. ©2011 AACR.-
dc.language.isoenen
dc.relation.urlhttp://cancerres.aacrjournals.org/content/71/5/1933.longen
dc.titleThe {Delta}Np63 Proteins Are Key Allies of BRCA1 in the Prevention of Basal-Like Breast Cancer.en
dc.typeArticle-
dc.contributor.departmentAuthors' Affiliations: Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, United Kingdom; Department of Surgery, Beaumont Hospital and Royal College of Surgeons in Ireland, Dublin, Ireland; Center for Molecular Pathology, Department of Laboratory Medicine, Malmö University Hospital, Lund University, Malmö, Sweden; and National Taiwan University of Science and Technology, Graduate institute of Bioengineering, Taipei, Taiwan.en
dc.identifier.journalCancer researchen
dc.description.provinceLeinster-

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