Although androgen-deprivation therapy is effective in inducing regression of androgen-dependent prostate cancer, relapse often occurs in an androgen-independent manner and is associated with poor prognosis. The mechanisms underlying castration resistance are not fully understood. Sung and colleagues from Shanghai Jiao Tong University, China, and Genentech, San Francisco, recently studied the potential contribution of androgen deprivation to epithelial–mesenchymal transition, a key developmental process that is also implicated in poor outcomes in a number of cancers, including prostate cancer.
The investigators found that both normal mouse prostate tissue and human LuCaP35 prostate tumor explants exhibit epithelial–mesenchymal transition as well as increased stem cell–like features following androgen deprivation. Further, they found a significant increase in mesenchymal markers (eg, VIMENTIN, ZEB1, CADHERIN11, FIBRONECTIN1) in prostate tumors from patients who had received androgen-deprivation therapy compared with patients who had not and despite variation in age and tumor grade among those who had received such treatment. Additional findings suggested that epithelial–mesenchymal transition was mediated by a bidirectional feedback loop involving the androgen receptor and the Zeb1 transcription factor, with each acting to inhibit the other.
Alternative Approach
According to Sung and colleagues, their study shows that “whereas androgen deprivation can effectively control prostate tumor size initially, it simultaneously promotes [epithelial–mesenchymal transition], an unintended consequence that may ultimately lead to castration resistance. Hence, a rational alternative approach [to treatment] may be to inhibit [epithelial–mesenchymal transition] in combination with [androgen-deprivation therapy] to prevent disease progression.”
In this regard, an antagonist to N-cadherin, a protein involved in epithelial–mesenchymal transition, has been shown to delay establishment of castration resistance. As the investigators noted, blocking epithelial–mesenchymal transition at a stage when castration resistance is already present may also be feasible since inhibition of Zeb1 may act to reverse epithelial–mesenchymal transition. ■
Sun Y, et al: Cancer Res 72:527-536, 2012.
