| 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. © 2006 by The National Academy of Sciences of the USA. |
| Keywords: |
signal transduction; mitogen activated protein kinase; protein kinase b; controlled study; unclassified drug; androgen; nonhuman; animal cell; mouse; animals; mice; animal tissue; cells, cultured; animal experiment; animal model; mice, mutant strains; transcription factor; cancer cell culture; enzyme activation; enzyme activity; cancer mortality; carcinogenesis; prostate cancer; prostatic neoplasms; prostate; phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase; carcinogenicity; proto-oncogene proteins c-akt; pten phosphohydrolase; prostate epithelium; stroma; extracellular signal-regulated map kinases; androgen receptor; rats; receptors, androgen; homeodomain protein; mouse strain; disease models, animal; b raf kinase; androgens; lethality; proto-oncogene proteins b-raf; akt signaling; hormone dependence; androgen independence; map kinase signaling; mouse models of cancer; transcription factor nkx3.1; androgen independent prostate cancer; hormone response
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