Combinatorial activities of Akt and B-Raf/Erk signaling in a mouse model of androgen-independent prostate cancer.
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 microenvironment. 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.
Gao
Hui
H
Center for Advanced Biotechnology and Medicine, Cancer Institute of New Jersey, and Department of Medicine, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, 679 Hoes Lane, Piscataway, NJ 08854, USA.
Ouyang
Xuesong
X
Banach-Petrosky
Whitney A
WA
Gerald
William L
WL
Shen
Michael M
MM
Abate-Shen
Cory
C
D000728:Androgens / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D051059:PTEN Phosphohydrolase / Q000172:deficiency; D011467:Prostate / Q000166:cytology / Q000473:pathology; D011471:Prostatic Neoplasms / Q000473:pathology*; D048493:Proto-Oncogene Proteins B-raf / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D011944:Receptors, Androgen / Q000378:metabolism; D015398:Signal Transduction
D000728:Androgens; D011944:Receptors, Androgen; D048493:Proto-Oncogene Proteins B-raf; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse