SPOP Mutation Drives Prostate Tumorigenesis In Vivo through Coordinate Regulation of PI3K/mTOR and AR Signaling

Publication date: 13 March 2017
Source:Cancer Cell, Volume 31, Issue 3
Author(s): Mirjam Blattner, Deli Liu, Brian D. Robinson, Dennis Huang, Anton Poliakov, Dong Gao, Srilakshmi Nataraj, Lesa D. Deonarine, Michael A. Augello, Verena Sailer, Lalit Ponnala, Michael Ittmann, Arul M. Chinnaiyan, Andrea Sboner, Yu Chen, Mark A. Rubin, Christopher E. Barbieri
Recurrent point mutations in SPOP define a distinct molecular subclass of prostate cancer. Here, we describe a mouse model showing that mutant SPOP drives prostate tumorigenesis in vivo. Conditional expression of mutant SPOP in the prostate dramatically altered phenotypes in the setting of Pten loss, with early neoplastic lesions (high-grade prostatic intraepithelial neoplasia) with striking nuclear atypia and invasive, poorly differentiated carcinoma. In mouse prostate organoids, mutant SPOP drove increased proliferation and a transcriptional signature consistent with human prostate cancer. Using these models and human prostate cancer samples, we show that SPOP mutation activates both PI3K/mTOR and androgen receptor signaling, effectively uncoupling the normal negative feedback between these two pathways.

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Teaser

Blattner et al. develop a mouse model and use it to demonstrate that human SPOP mutation can drive prostate tumorigenesis through coordinate deregulation of both PI3K/mTOR and AR pathways. The study provides insights to both unique and common features of molecular subtypes of human prostate cancer.


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