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Int J Biol Sci. 2014 Jun 10;10(6):627-42. doi: 10.7150/ijbs.8756. eCollection 2014.

Conversion of androgen receptor signaling from a growth suppressor in normal prostate epithelial cells to an oncogene in prostate cancer cells involves a gain of function in c-Myc regulation.

Author information

1
1. Chemical Therapeutics Program, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins. ; 3. The Brady Urological Institute, Johns Hopkins.
2
1. Chemical Therapeutics Program, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins. ; 2. Cellular and Molecular Medicine Graduate Program at Johns Hopkins.
3
1. Chemical Therapeutics Program, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins. ; 2. Cellular and Molecular Medicine Graduate Program at Johns Hopkins. ; 3. The Brady Urological Institute, Johns Hopkins.

Abstract

In normal prostate, androgen-dependent androgen receptor (AR) signaling within prostate stromal cells induces their secretion of paracrine factors, termed "andromedins" which stimulate growth of the epithelial cells. The present studies demonstrate that androgen-dependent andromedin-driven growth stimulation is counter-balanced by androgen-induced AR signaling within normal adult prostate epithelial cells resulting in terminal G0 growth arrest coupled with terminal differentiation into ΔNp63-negative, PSA-expressing secretory luminal cells. This cell autonomous AR-driven terminal differentiation requires DNA-binding of the AR protein, is associated with decreases in c-Myc m-RNA and protein, are coupled with increases in p21, p27, and SKP-2 protein expression, and does not require functional p53. These changes result in down-regulation of Cyclin D1 protein and RB phosphoryation. shRNA knockdown documents that neither RB, p21, p27 alone or in combination are required for such AR-induced G0 growth arrest. Transgenic expression of a constitutive vector to prevent c-Myc down-regulation overrides AR-mediated growth arrest in normal prostate epithelial cells, which documents that AR-induced c-Myc down-regulation is critical in terminal growth arrest of normal prostate epithelial cells. In contrast, in prostate cancer cells, androgen-induced AR signaling paradoxically up-regulates c-Myc expression and stimulates growth as documented by inhibition of both of these responses following exposure to the AR antagonist, bicalutamide. These data document that AR signaling is converted from a growth suppressor in normal prostate epithelial cells to an oncogene in prostate cancer cells during prostatic carcinogenesis and that this conversion involves a gain of function for regulation of c-Myc expression.

KEYWORDS:

Androgen Receptor; Human Prostate Cancer; MYC.; Oncogene; Tumor Suppressor

PMID:
24948876
PMCID:
PMC4062956
DOI:
10.7150/ijbs.8756
[Indexed for MEDLINE]
Free PMC Article

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