title: 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.
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.
authors.affiliation: 1. Chemical Therapeutics Program, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins. ; 3. The Brady Urological Institute, Johns Hopkins.
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Vander Griend
authors.affiliation: 1. Chemical Therapeutics Program, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins. ; 2. Cellular and Molecular Medicine Graduate Program at Johns Hopkins.
authors.forename: Ivan V
authors.initials: IV
authors.lastname: Litvinov
authors.affiliation: 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.
authors.forename: John T
authors.initials: JT
authors.lastname: Isaacs
mesh_terms: D045744:Cell Line, Tumor; D004847:Epithelial Cells / Q000166:cytology* / Q000378:metabolism*; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology
chemical_list: C410798:AR protein, human; D016271:Proto-Oncogene Proteins c-myc; D011944:Receptors, Androgen
keywords: Androgen Receptor; Human Prostate Cancer; MYC.; Oncogene; Tumor Suppressor