Androgen Deprivation Causes Epithelial–Mesenchymal Transition in the Prostate: Implications for Androgen-Deprivation Therapy

Abstract

Androgen deprivation is currently a standard-of-care, first-line therapy for prostate cancer in the United States. Although this regimen effectively regresses androgen-dependent disease, relapse often occurs in an androgenindependent manner and is associated with poor prognosis. Such castration-resistant prostate cancer represents a major clinical challenge, and the mechanisms underlying castration resistance are not fully understood. Epithelial-mesenchymal transition (EMT) is a key developmental process and has also been implicated in cancer metastasis and therapeutic resistance in recent years. However, the factors contributing to EMT in human cancers remain unclear. Here, we show that both normal mouse prostate tissue and human LuCaP35 prostate tumor explants display an EMT as well as increased stem cell-like features following androgen deprivation. Importantly, we observed similar changes in mesenchymal features in prostate tumors from patients treated with androgen-deprivation therapy. In addition, we have delineated a feedback loop involving the androgen receptor and the Zeb1 transcription factor that seems to mediate this transition. In summary, we show for the first time that androgen deprivation induces EMT in both normal prostate and prostate cancer, revealing a potentially important consequence of a standard-of-care treatment for prostate cancer. This finding could have significant implications for second-line treatment strategies in this clinical setting. Cancer Res; 72(2); 527-36. Ó2011 AACR.

Crosstalk between epithelial-mesenchymal transition and castration resistance mediated by Twist1/AR signaling in prostate cancer

“…As well, TGF-b1 expression was also shown to be induced by androgen deprivation in human prostatic tissues (Fuzio et al 2012). We and others have shown that the EMT-regulating transcription factor Twist1 was induced by androgen deprivation (Shiota et al 2012b, Sun et al 2012. Furthermore, CRPC tumors from LNCaP-xenograft model using castrated mice showed augmented AR signaling as well as an EMT phenotype, characterized by increased expression of Twist1 as well as other mesenchymal markers.…”

EC-70124, a Novel Glycosylated Indolocarbazole Multikinase Inhibitor, Reverts Tumorigenic and Stem Cell Properties in Prostate Cancer by Inhibiting STAT3 and NF-κB

“…Thus, targeting these transcription factors might provide an effective way to contrast the expansion of the highly tumorigenic stem-like tumor cells in advanced prostate cancer. CSCs are intrinsically resistant to androgen deprivation therapy and many cytotoxic drugs causing treatment failures and disease recurrence (8)(9)(10)49). CSC-targeted agents could be most effective in combination with current therapies to increase response rates and prolong survival in advanced prostate cancer patients (11,12).…”

Epithelial-to-Mesenchymal Transition Mediates Docetaxel Resistance and High Risk of Relapse in Prostate Cancer

“…The expression of the transcription factor ZEB1 may be induced by dihydrotestosterone and is mediated by two androgen-response elements (40). Recently, Sun and colleagues showed that androgen deprivation causes EMT in animal models and in tumor samples of patients treated with hormone therapy (41). Moreover, the presence of AR-truncated isoforms, which are increased in the castration-resistant progression, regulate the expression of EMT (42).…”