Research Oncology, Genentech, 1 DNA Way, San Francisco, CA, 94080, United States.
Androgen deprivation is currently a standard of care, front line therapy for prostate cancer in the US. 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 demonstrate 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 appears 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 could have significant implications for second-line treatment strategies in this clinical setting.
Written by:
Sun Y, Wang BE, Leong KG, Yue P, Li L, Jhunjhunwala S, Chen D, Seo K, Modrusan Z, Gao WQ, Settleman J, Johnson L. Are you the author?
Reference: Cancer Res. 2011 Nov 22. Epub ahead of print.
doi: 10.1158/0008-5472.CAN-11-3004
PubMed Abstract
PMID: 22108827
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