Androgen deprivation causes epithelial–mesenchymal transition (EMT) in both healthy and cancerous prostate tissue, according to a team of researchers from San Francisco, USA. This process is thought to be mediated by a negative feedback loop between the androgen receptor and Zeb1.
In the first set of experiments, Sun et al. evaluated the gene expression profiles of intact and castrated mouse prostates. 3 days postcastration, N-cadherin, Twist1 and Slug expression levels were upregulated. These increases were reversed upon testosterone replenishment. Similar changes were observed in tumor biopsies from patients and SLUG was one of the top-ranking genes for expression status 14 days after chemical castration.
In further work, xenografts of LuCaP35—derived from a lymph node metastasis of prostate cancer—were transplanted onto mice. Those with established grafts were castrated, and regressed tumors were isolated 4 weeks later. Gene expression profiling revealed activated TGFβ signaling in regressed cancers, as well as increased expression of several EMT-inducing genes and two 'stemness' markers (WNT5a and WNT5b). 'In vitro castration'—achieved by depriving LNCaP cells of hormones—produced slow-growing cells that formed spheres and adhered poorly to plates.
In all studies, androgen deprivation resulted in increased ZEB1 expression, suggesting a key role for this gene in EMT. Androgen receptor and Zeb1 expression are mutually exclusive of each other and the group identified a bidirectional negative feedback loop that mediates castration-induced EMT.
These findings could have significant implications for prostate cancer therapy as EMT has been linked to therapeutic resistance and a poor prognosis. Thus, patients receiving androgen deprivation therapy might benefit from concomitant treatment with an EMT inhibitor. In support of this theory, a novel drug targeting N-cadherin has been shown to delay the onset of castration resistance.
“The monoclonal antibodies targeting N-cadherin are encouraging, though toxicity may ultimately limit their utility,” says Leisa Johnson, who coordinated the work done by Sun et al. “Many of the most attractive players are transcription factors (for example, ZEB1, TWIST1, and SLUG) that have notoriously proved difficult to target therapeutically. RNAi-based therapeutics hold promise, though successful delivery still remains their biggest challenge. Whether targeting ZEB1 could resensitize castration-resistant prostate cancer to androgen deprivation therapy remains to be determined.”
ORIGINAL RESEARCH PAPER
Sun, Y. et al. Androgen deprivation causes epithelial-mesenchymal transition in the prostate: implications for androgen-deprivation therapy. Cancer Res. doi:10.1158/0008-5472.CAN-11-3004
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Clyne, M. Androgen deprivation causes EMT in the prostate. Nat Rev Urol 9, 4 (2012). https://doi.org/10.1038/nrurol.2011.208
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DOI: https://doi.org/10.1038/nrurol.2011.208
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