Amplification of SOX4 promotes PI3K/Akt signaling in human breast cancer.
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.
Rutgers Cancer Institute of New Jersey, 195 Little Albany Street, CINJ 4558, New Brunswick, NJ, 08903, USA.|Department of Radiation Oncology, Robert Wood Johnson Medical School, New Brunswick, NJ, USA.|Rutgers, The State University of New Jersey, New Brunswick, NJ, USA.
Gaurav A
GA
Mehta
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Joel S
JS
Parker
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Grace O
GO
Silva
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Katherine A
KA
Hoadley
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Charles M
CM
Perou
Rutgers Cancer Institute of New Jersey, 195 Little Albany Street, CINJ 4558, New Brunswick, NJ, 08903, USA. michael.gatza@cinj.rutgers.edu.|Department of Radiation Oncology, Robert Wood Johnson Medical School, New Brunswick, NJ, USA. michael.gatza@cinj.rutgers.edu.|Rutgers, The State University of New Jersey, New Brunswick, NJ, USA. michael.gatza@cinj.rutgers.edu.
Michael L
ML
Gatza
D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D019295:Computational Biology / Q000379:methods; D056915:DNA Copy Number Variations; D030541:Databases, Genetic; D005260:Female; D005784:Gene Amplification; D020869:Gene Expression Profiling; D006801:Humans; D018295:Neoplasms, Basal Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D055751:SOXC Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D059467:Transcriptome
C083431:SOX4 protein, human; D055751:SOXC Transcription Factors; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt
Akt; Breast cancer; Genomics; PI3 kinase; SOX4