AKT regulates BRCA1 stability in response to hormone signaling

Andrew C. Nelson, Traci R. Lyons, Christian D. Young, Kirk C. Hansen, Steven M. Anderson, Jeffrey T. Holt

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

Abstract

The observation that inherited mutations within BRCA1 result in breast and ovarian cancers suggests a functional relationship may exist between hormone signaling and BRCA1 function. We demonstrate that AKT activation promotes the expression of BRCA1 in response to estrogen and IGF-1 receptor signaling, and the rapid increase in BRCA1 protein levels appears to occur independently of new protein synthesis. Further, we identify a novel AKT phosphorylation site in BRCA1 at S694 which is responsive to activation of these signaling pathways. These data suggest AKT phosphorylation of BRCA1 increases total protein expression by preventing proteasomal degradation. AKT activation also appears to support nuclear localization of BRCA1, and co-expression of activated AKT with BRCA1 decreases radiation sensitivity, suggesting this interaction has functional consequences for BRCA1's role in DNA repair. Targets within this pathway could provide strategies for modulation of BRCA1 protein, which may prove therapeutically beneficial for breast and ovarian cancer treatment.

Original languageEnglish (US)
Pages (from-to)129-142
Number of pages14
JournalMolecular and Cellular Endocrinology
Volume319
Issue number1-2
DOIs
StatePublished - May 5 2010

Bibliographical note

Funding Information:
This work was funded by grants from the Department of Defense Breast Cancer Research Program W81XWH-06-1-0335 to ACN, DAMD17-02-1-0351 to TRL, W81XWH-06-1-0423 to CDY, and from the Public Health Service DK063674 to SMA. The authors wish to thank: Ms. Maria Wong and Ms. Rita Lieberman for technical laboratory assistance, Ms. Lisa Litzenberger for preparation of the figures, Dr. Jerome Schaack for assistance with recombinant adenovirus production, Drs. David Orlicky and James McManaman for assistance with microscopy, Ms. Lauren Kiemele for assistance with mass spectroscopy, and Mr. Michael Rudolph and Dr. Wilbur Franklin for assistance with qPCR. Bortezomib was provided by Dr. Stuart Lind. The Proteomics and Flow Cytometry Core Laboratories at the University of Colorado Cancer Center contributed to this work. Appendix A

Keywords

  • AKT
  • BRCA1
  • Breast cancer
  • Estrogen
  • IGF1
  • Phosphorylation
  • Proteasome

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