Journal
BREAST CANCER RESEARCH AND TREATMENT
Volume 162, Issue 3, Pages 439-450Publisher
SPRINGER
DOI: 10.1007/s10549-017-4139-2
Keywords
Breast cancer; Genomics; SOX4; PI3 kinase; Akt
Categories
Funding
- National Cancer Institute of the US National Institutes of Health [R00-CA166228]
- V Foundation for Cancer Research [V2016-013]
- New Jersey Health Foundation [PC-52-16]
- National Cancer Institute of the US National Institutes of Health Breast SPORE program [P50-CA58223-09A1, R01-CA148761-04]
- Susan G. Komen for the Cure
- Breast Cancer Research Foundation
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The PI3K/Akt signaling axis contributes to the dysregulation of many dominant features in breast cancer including cell proliferation, survival, metabolism, motility, and genomic instability. While multiple studies have demonstrated that basal-like or triple-negative breast tumors have uniformly high PI3K/Akt activity, genomic alterations that mediate dysregulation of this pathway in this subset of highly aggressive breast tumors remain to be determined. In this study, we present an integrated genomic analysis based on the use of a PI3K gene expression signature as a framework to analyze orthogonal genomic data from human breast tumors, including RNA expression, DNA copy number alterations, and protein expression. In combination with data from a genome-wide RNA-mediated interference screen in human breast cancer cell lines, we identified essential genetic drivers of PI3K/Akt signaling. Our in silico analyses identified SOX4 amplification as a novel modulator of PI3K/Akt signaling in breast cancers and in vitro studies confirmed its role in regulating Akt phosphorylation. Taken together, these data establish a role for SOX4-mediated PI3K/Akt signaling in breast cancer and suggest that SOX4 may represent a novel therapeutic target and/or biomarker for current PI3K family therapies.
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