The use of androgen deprivation therapy and second line anti-androgens in prostate cancer has led to the emergence of tumors employing multiple androgen receptor (AR)-dependent and AR-independent mechanisms to resist AR targeted therapies in castration-resistant prostate cancer (CRPC). While the AR signaling axis remains the cornerstone for therapeutic development in CRPC, a clearer understanding of the heterogeneous biology of CRPC tumors is needed for inno-vative treatment strategies. In this review, we discuss the characteristics of CRPC tumors that lack AR activity and the temporal and spatial considerations for the conversion of an AR-dependent to an AR-independent tumor type. We describe the more prevalent treatment-emergent phenotypes aris-ing in the CRPC disease continuum, including amphicrine, AR-low, double-negative, neuroendo-crine and small cell phenotypes. We discuss the association between the loss of AR activity and tumor plasticity with a focus on the roles of transcription factors like SOX2, DNA methylation, alterna-tive splicing, and the activity of epigenetic modifiers like EZH2, BRD4, LSD1, and the nBAF complex in conversion to a neuroendocrine or small cell phenotype in CRPC. We hypothesize that only a subset of CRPC tumors have the propensity for tumor plasticity and conversion to the neuroendo-crine phenotype and outline how we might target these plastic and emergent phenotypes in CRPC. In conclusion, we assess the current and future avenues for treatment and determine that the heter-ogeneity of CRPCs lacking AR activity will require diverse treatment approaches.
Mark P Labrecque, Joshi J Alumkal, Ilsa M Coleman, Peter S Nelson, and Colm Morrissey
Oliver Zierau, Jacintha O’Sullivan, Colm Morrissey, Dana McDonald, Winfried Wünsche, Martin R Schneider, Martin P Tenniswood, and Günter Vollmer
Tamoxifen is the most widely prescribed anti-neoplastic drug for the treatment of both localized and metastatic breast cancer. It is also the prototype for a class of drugs that are referred to as selective estrogen receptor modifiers (SERMs), most of which have both estrogenic and anti-estrogenic activity in estrogen target tissues including the breast and endometrium. The underlying mechanisms of action of SERMs in the breast and endometrium that lead to profound differences in the tissue-specific effects of tamoxifen have not yet been elucidated.
We have compared the effects of tamoxifen and the pure anti-estrogen ICI 182,780 (Faslodex) in the RUCA-I hormone-responsive rat endometrial cell line in vitro and in vivo. In cell culture, RUCA-I cells responded to both estrogens and anti-estrogens, and the expression of clusterin and complement C3 mRNAs required the presence of estradiol and was repressed in the absence of estradiol or in the presence of the pure anti-estrogen ICI 182,780. Tamoxifen, on the other hand, induced both complement C3 and clusterin mRNA in the absence of estradiol and failed to repress their expression in the presence of estradiol. When grown as subcutaneous xenografts in syngeneic Da/Han rats for 5 weeks, the RUCA-I cells retained their sensitivity to estradiol, as demonstrated by significantly enhanced tumor growth in intact female rats compared with the growth in ovariectomized rats. But neither ICI 182,780 nor tamoxifen had a significant impact on tumor growth in cycling or ovariectomized animals. On the other hand, tamoxifen was potently estrogenic in metastatic lymph nodes, increasing the size of the lymph node tumors almost 6-fold over that seen in the intact cycling animals. In primary tumors, the expression of complement C3 mirrored that seen in vitro, although tamoxifen showed some agonist activity in ovariectomized animals. Tamoxifen also displayed marked agonist activity with respect to clusterin expression and enhanced clusterin mRNA levels and protein in both the primary tumors and lymph metastases in intact and ovariectomized animals.
Given the recent demonstration that over-expression of clusterin increases the metastatic potential of breast cancer cells, these data may provide a mechanistic explanation for the increased incidence of endometrial cancer in postmenopausal patients treated with tamoxifen.