1. Combinatorial activities of Akt and B-Raf/Erk signaling in a mouse model of androgen-independent prostate cancer
- Author
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Gao, Hui, Ouyang, Xuesong, Banach-Petrosky, Whitney A., Gerald, William L., Shen, Michael M., and Abate-Shen, Cory
- Subjects
Androgens -- Research ,Protein kinases -- Structure ,Protein kinases -- Research ,Cellular signal transduction -- Research ,Cancer cells -- Research ,Science and technology - Abstract
Androgen independence is responsible for most prostate cancer lethality, yet currently there are no effective clinical treatments. We have been investigating the mechanisms underlying androgen-independent prostate cancer in Nkx3.1;Pten mutant mice, which display salient features of the disease, including a requirement for wild-type androgen receptor (AR) signaling. We now demonstrate that the Akt and Erk MAP kinase signaling pathways are activated in androgen-independent lesions of these mice. Forced activation of either Akt or Erk signaling in an androgen-responsive prostate cancer cell line promotes hormone-independent but AR-dependent growth in culture. Although these pathways act additively in culture, they act synergistically in vivo to promote tumorigenicity and androgen independence in the context of the prostate micro-environment. We propose that androgen independence emerges by means of epithelial--stromal competition, in which activation of Akt and Erk promotes AR activity in the prostate epithelium while counteracting antagonistic effects of the stroma. Akt signaling | androgen independence | MAP kinase signaling | mouse models of cancer
- Published
- 2006