title: 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 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.
authors: Department of Discovery Oncology, Genentech Inc., South San Francisco, California, USA.
authors: Yuting
authors: Y
authors: Sun
authors: Bu-Er
authors: BE
authors: Wang
authors: Kevin G
authors: KG
authors: Leong
authors: Peng
authors: P
authors: Yue
authors: Li
authors: L
authors: Li
authors: Suchit
authors: S
authors: Jhunjhunwala
authors: Darrell
authors: D
authors: Chen
authors: Kyounghee
authors: K
authors: Seo
authors: Zora
authors: Z
authors: Modrusan
authors: Wei-Qiang
authors: WQ
authors: Gao
authors: Jeffrey
authors: J
authors: Settleman
authors: Leisa
authors: L
authors: Johnson
mesh_terms: D000728:Androgens / Q000172:deficiency*; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004847:Epithelial Cells / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009362:Neoplasm Metastasis; D009376:Neoplasms, Hormone-Dependent; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D009919:Orchiectomy; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000628:therapy*; D011944:Receptors, Androgen / Q000378:metabolism; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
chemical_list: D000728:Androgens; D011944:Receptors, Androgen