Journal article
Identifi cation of pik3ca mutation as a genetic driver of prostate cancer that cooperates with pten loss to accelerate progression and castration-resistant growth
HB Pearson, J Li, VS Meniel, CM Fennell, P Waring, KG Montgomery, RJ Rebello, AA Macpherson, S Koushyar, L Furic, C Cullinane, RW Clarkson, MJ Smalley, KJ Simpson, TJ Phesse, PR Shepherd, PO Humbert, OJ Sansom, WA Phillips
Cancer Discovery | AMER ASSOC CANCER RESEARCH | Published : 2018
Abstract
Genetic alterations that potentiate PI3K signaling are frequent in prostate cancer, yet how different genetic drivers of the PI3K cascade contribute to prostate cancer is unclear. Here, we report PIK3CA mutation/amplifi cation correlates with poor survival of patients with prostate cancer. To interrogate the requirement of different PI3K genetic drivers in prostate cancer, we employed a genetic approach to mutate Pik3ca in mouse prostate epithelium. We show Pik3ca H1047R mutation causes p110α-dependent invasive prostate carcinoma in vivo. Furthermore, we report that PIK3CA mutation and PTEN loss coexist in patients with prostate cancer and can cooperate in vivo to accelerate disease progress..
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Awarded by Cardiff University
Funding Acknowledgements
This work was generously supported by a Prostate Cancer Foundation of Australia concept grant (#CG 1611) and an NHMRC project grant (#1080491) awarded to W.A. Phillips, and a Peter MacCallum Cancer Foundation grant (#1520) awarded to H.B. Pearson. H.B. Pearson is supported by a Marie Sklodowska Curie Actions/Ser Cymru II/Horizons 2020 COFUND fellowship (#663830-CU-041). T.J. Phesse is supported by a Capital Medical University/Cardiff University Fellowship. L. Furic is supported by the Department of Health and Human Services acting through the Victorian Cancer Agency (MCRF16007). P.O. Humbert is supported by an NHMRC Senior Research Fellowship (#1079133). The Victorian Centre for Functional Genomics (VCFG) and the RPPA platform (K. J. Simpson) is funded by the Australian Cancer Research Foundation (ACRF), the Australian Phenomics Network (APN) through funding from the Australian Government's National Collaborative Research Infrastructure Strategy (NCRIS) program, the Peter MacCallum Cancer Foundation, and the University of Melbourne Collaborative Research Infrastructure Program. The authors wish to thank the animal, bioinformatics, VCFG-RPPA, microscopy, and histology core facilities at the Peter MacCallum Cancer Centre for supporting this project, and the histology departments at the Beatson Institute of Cancer Research and the European Cancer Stem Cell Research Centre. We also thank Nathan Crouch (VCFG-RPPA) for bioinformatics analysis of RPPA data, as well as Samantha McIntosh, Kerry Ardley, Susan Jackson, Lauren Dawes, Stephanie Le, Katherine Papastratos, and Qerime Mundrea at the Peter MacCallum Cancer Centre, Rachel Ridgway at the Beatson Institute for Cancer Research, and Derek Scarborough at The School of Biosciences, Cardiff University, for their technical assistance.