GENETICS OF PROSTATE CANCER

A genetically engineered mouse model developed by Blattner et al investigating the role of the gene Speckle Type BTB/POZ Protein, or SPOP, as a driver of prostate cancer has found that the mutation drives prostate neoplasia through coordinate deregulation of both P13K/mTOR and androgen receptor (AR)-signaling pathways. These pathways are important to cell survival and growth and are processes that contribute to malignancy. The findings provide insight into both the unique and common features of molecular subtypes of prostate cancer and highlight potential opportunities for precision therapy. The study was published in Cancer Cell.

Study Methodology

To determine the impact of SPOP mutation in the prostate, the researchers developed a transgenic mouse with prostate-specific conditional expression of SPOP-F133V, a common missense mutation found in human prostate cancer. The mice were crossed with PbCre4 mice to express mutant SPOP specifically in the prostate.

Study Findings

The mouse model showed 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, the researchers showed that SPOP mutation activates both PI3K/mTOR and androgen receptor signaling, effectively uncoupling the normal negative feedback between these two pathways.

Study Significance

“Our findings show that SPOP mutation drives prostate neoplasia in vivo through coordinate deregulation of both P13K/mTOR and AR pathways. The discovery that SPOP mutation can activate two of the major pathways in prostate cancer exposes not only the biology of the SPOP mutant subclass, but the central importance of these pathways and their context across the spectrum of prostate cancer. These findings provide insight into both the unique and common features of molecular subtypes of human prostate cancer and highlight potential opportunities for precision therapy,” concluded the study authors.

“This [finding] is important because now we have to think about SPOP cancers differently. This may have implications for how people respond to treatment and how amenable they are to certain drugs,” said Mark A. Rubin, MD, Director of the Caryl and Israel Englander Institute for Precision Medicine at Weill Cornell Medicine, and coauthor of this study, in a statement.

Mark A. Rubin, MD, and Christopher E. Barbieri, MD, PhD, of Weill Cornell Medicine, are the corresponding authors of this study.