Key cellular pathway in prostate cancer identified

The protein SPOP (speckle-type poxvirus and zinc finger [POZ] domain protein), which is most frequently mutated in human prostate cancers, is a key regulator of androgen receptor activity that prevents uncontrolled growth of cells in the prostate and thus helps prevent cancer. This finding sheds light on a new mechanism by which prostate cancer develops in men. Central to the development of nearly all prostate cancer cases are malfunctions in the androgen receptor—the cellular component that binds to male hormones.

Prostate cancer is the second most common cause of cancer in men and the second leading cause of cancer death in American men, with more than 913,000 new cases and more than 261,000 deaths worldwide each year. Because of the widespread disability and death that prostate cancer causes, finding new strategies to develop better treatments is an important public health goal.

The androgen receptor is essential for normal prostate cell growth and survival. It is also important for initiation and progression of prostate cancer. Androgen deprivation therapy, including chemical castration and/or antiandrogen therapy, is the mainstay for treating advanced/disseminated prostate cancer. However, tumors almost always recur 2 to 3 years after initial response and relapse into castration-resistant prostate cancer. Development of this therapy-resistant cancer is related to the persistent activation of androgen receptors.

"By uncovering this new and important pathway of androgen receptor destruction, we may one day be able to develop more effective treatments for a substantial proportion of prostate cancer patients who have developed resistance to standard antiandrogen therapy," said senior author Haojie Huang, PhD, a Mayo Clinic biochemist in Rochester, Minnesota. The study was published in Cell Reports (2014; doi:10.1016/j.celrep.2014.01.013).

SPOP mutations have been detected in approximately 15% of prostate cancer cases. In addition, it has been shown that, in about 35% of prostate cancers, the SPOP protein is expressed at abnormally low levels. Despite its prevalence in prostate cancer, it was not known whether or how SPOP defects contributed to tumor development.

What the research team discovered is that SPOP is an enzyme that selectively destroys the androgen receptor protein. Failure to do so due to alterations in SPOP results in an overabundance of androgen receptor, a master regulator of prostate cancer cell growth.

The major discoveries of this study are that the antiandrogen receptor is a bona fide degradation substrate of SPOP, androgen-receptor splicing variants are resistant to SPOP-mediated degradation, and prostate–cancer-associated SPOP mutants cannot bind to and promote androgen receptor degradation. Finally, androgens antagonize, but antiandrogens promote, SPOP-mediated degradation of androgen receptor.

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