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 androgen-independent 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.
Highlights
Prostate cancer is the most frequently diagnosed cancer in men in the United States, accounting for 10% of all cancerrelated deaths [1]
Considering the conceptual association between stem cells and Epithelial–mesenchymal transition (EMT), we hypothesized that the castrated prostate tissue may undergo an EMT
We have examined the effect of androgen deprivation on a wide variety of both normal prostate and prostate cancer model systems
Summary
Prostate cancer is the most frequently diagnosed cancer in men in the United States, accounting for 10% of all cancerrelated deaths [1]. Androgen-deprivation therapy is a standardof-care treatment for prostate cancer and efficiently controls the growth of androgen-dependent tumors. The majority of these cancers become refractory. Authors' Affiliations: Departments of 1Discovery Oncology, 2Molecular Biology, 3Research Oncology, and 4Bioinformatics, Genentech Inc., South San Francisco, California. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). Gao: Renji-Med X Clinical Stem Cell Research Center and Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, 1630 Dongfang Road, Shanghai 200127, China. The expression microarray data have been deposited in the GEO database under accession numbers GSE33316 and GSE33317
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