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

Buckley, Niamh E; Conlon, Susan J; Jirström, Karin LU ; Kay, Elaine W; Crawford, Nyree T; O'Grady, Anthony; Sheehan, Katherine; Mc Dade, Simon S; Wang, Ching-Wei and McCance, Dennis J, et al. (2011) In Cancer Research 71(5). p.1933-1944
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... (More)
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. (Less)
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Cancer Research
volume
71
issue
5
pages
1933 - 1944
publisher
American Association for Cancer Research Inc.
external identifiers
  • wos:000287845300043
  • pmid:21363924
  • scopus:79952237500
ISSN
1538-7445
DOI
10.1158/0008-5472.CAN-10-2717
language
English
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yes
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9a584e93-9438-4d01-b961-035a630b6296 (old id 1884497)
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http://www.ncbi.nlm.nih.gov/pubmed/21363924?dopt=Abstract
date added to LUP
2011-04-01 11:51:40
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2017-06-04 04:10:54
@article{9a584e93-9438-4d01-b961-035a630b6296,
  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.},
  author       = {Buckley, Niamh E and Conlon, Susan J and Jirström, Karin and Kay, Elaine W and Crawford, Nyree T and O'Grady, Anthony and Sheehan, Katherine and Mc Dade, Simon S and Wang, Ching-Wei and McCance, Dennis J and Johnston, Patrick G and Kennedy, Richard D and Harkin, D Paul and Mullan, Paul B},
  issn         = {1538-7445},
  language     = {eng},
  number       = {5},
  pages        = {1933--1944},
  publisher    = {American Association for Cancer Research Inc.},
  series       = {Cancer Research},
  title        = {The {Delta}Np63 Proteins Are Key Allies of BRCA1 in the Prevention of Basal-Like Breast Cancer.},
  url          = {http://dx.doi.org/10.1158/0008-5472.CAN-10-2717},
  volume       = {71},
  year         = {2011},
}