Gaurav A Mehta1,2,3, Joel S Parker4, Grace O Silva4, Katherine A Hoadley4, Charles M Perou4, Michael L Gatza5,6,7. 1. Rutgers Cancer Institute of New Jersey, 195 Little Albany Street, CINJ 4558, New Brunswick, NJ, 08903, USA. 2. Department of Radiation Oncology, Robert Wood Johnson Medical School, New Brunswick, NJ, USA. 3. Rutgers, The State University of New Jersey, New Brunswick, NJ, USA. 4. Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. 5. Rutgers Cancer Institute of New Jersey, 195 Little Albany Street, CINJ 4558, New Brunswick, NJ, 08903, USA. michael.gatza@cinj.rutgers.edu. 6. Department of Radiation Oncology, Robert Wood Johnson Medical School, New Brunswick, NJ, USA. michael.gatza@cinj.rutgers.edu. 7. Rutgers, The State University of New Jersey, New Brunswick, NJ, USA. michael.gatza@cinj.rutgers.edu.
Abstract
PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
PURPOSE: 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. METHODS: 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 humanbreast tumors, including RNA expression, DNA copy number alterations, and protein expression. In combination with data from a genome-wide RNA-mediated interference screen in humanbreast cancer cell lines, we identified essential genetic drivers of PI3K/Akt signaling. RESULTS: 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. CONCLUSIONS: 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.
Entities:
Keywords:
Akt; Breast cancer; Genomics; PI3 kinase; SOX4
Authors: José Baselga; Mario Campone; Martine Piccart; Howard A Burris; Hope S Rugo; Tarek Sahmoud; Shinzaburo Noguchi; Michael Gnant; Kathleen I Pritchard; Fabienne Lebrun; J Thaddeus Beck; Yoshinori Ito; Denise Yardley; Ines Deleu; Alejandra Perez; Thomas Bachelot; Luc Vittori; Zhiying Xu; Pabak Mukhopadhyay; David Lebwohl; Gabriel N Hortobagyi Journal: N Engl J Med Date: 2011-12-07 Impact factor: 91.245
Authors: Michael L Gatza; Joseph E Lucas; William T Barry; Jong Wook Kim; Quanli Wang; Matthew D Crawford; Michael B Datto; Michael Kelley; Bernard Mathey-Prevot; Anil Potti; Joseph R Nevins Journal: Proc Natl Acad Sci U S A Date: 2010-03-24 Impact factor: 11.205
Authors: M Piccart; G N Hortobagyi; M Campone; K I Pritchard; F Lebrun; Y Ito; S Noguchi; A Perez; H S Rugo; I Deleu; H A Burris; L Provencher; P Neven; M Gnant; M Shtivelband; C Wu; J Fan; W Feng; T Taran; J Baselga Journal: Ann Oncol Date: 2014-09-17 Impact factor: 32.976
Authors: Ian G Campbell; Sarah E Russell; David Y H Choong; Karen G Montgomery; Marianne L Ciavarella; Christine S F Hooi; Briony E Cristiano; Richard B Pearson; Wayne A Phillips Journal: Cancer Res Date: 2004-11-01 Impact factor: 12.701
Authors: Yoichi Nagata; Keng-Hsueh Lan; Xiaoyan Zhou; Ming Tan; Francisco J Esteva; Aysegul A Sahin; Kristine S Klos; Ping Li; Brett P Monia; Nina T Nguyen; Gabriel N Hortobagyi; Mien-Chie Hung; Dihua Yu Journal: Cancer Cell Date: 2004-08 Impact factor: 31.743
Authors: Parham Ramezani-Rad; Huimin Geng; Christian Hurtz; Lai N Chan; Zhengshan Chen; Hassan Jumaa; Ari Melnick; Elisabeth Paietta; William L Carroll; Cheryl L Willman; Véronique Lefebvre; Markus Müschen Journal: Blood Date: 2012-11-14 Impact factor: 22.113
Authors: Lao H Saal; Peter Johansson; Karolina Holm; Sofia K Gruvberger-Saal; Qing-Bai She; Matthew Maurer; Susan Koujak; Adolfo A Ferrando; Per Malmström; Lorenzo Memeo; Jorma Isola; Pär-Ola Bendahl; Neal Rosen; Hanina Hibshoosh; Markus Ringnér; Ake Borg; Ramon Parsons Journal: Proc Natl Acad Sci U S A Date: 2007-04-23 Impact factor: 11.205
Authors: Victor J Weigman; Hann-Hsiang Chao; Andrey A Shabalin; Xiaping He; Joel S Parker; Silje H Nordgard; Tatyana Grushko; Dezheng Huo; Chika Nwachukwu; Andrew Nobel; Vessela N Kristensen; Anne-Lise Børresen-Dale; Olufunmilayo I Olopade; Charles M Perou Journal: Breast Cancer Res Treat Date: 2011-11-03 Impact factor: 4.872
Authors: Pierre-Antoine Bissey; Mona Teng; Jacqueline H Law; Wei Shi; Jeff P Bruce; Valentin Petit; Sai W Tsao; Kenneth W Yip; Fei-Fei Liu Journal: BMC Cancer Date: 2020-06-26 Impact factor: 4.430