The human prostate is androgen dependent and prostate cancer (CaP) maintains this dependence on androgens. It undergoes apoptosis and regression following androgen withdrawal but eventually recurs in the absence of testicular androgens. We are studying a human CaP xenograft (CWR22) that retains these biological characteristics including regression following androgen withdrawal and recurrence after several months in the absence of androgen. Following the withdrawal of androgen stimulation, androgen receptor (AR) levels decrease in CWR22. However, the recurrent tumor CWR22R expresses a high level of AR relative to the androgen- withdrawn CWR22. In the recurrent tumor AR exhibits intense nuclear immunostaining suggests it is activated in the absence of androgen. Moreover, androgen-regulated mRNAs that decreased following androgen withdrawal are up-regulated in CWR22R in the absence of androgen stimulation. The goal of the research will be to establish the role of AR in mediating recurrent gene expression and cellular growth using the CWR22/CWR22R model.
Specific Aims of this part of the proposal are to: 1. Identify mechanisms controlling the different steady state expression levels of AR mRNA and protein in androgen withdrawn CWR22 and CWR22R. 2. Determine the activation state of AR in the recurrent tumor, CW22R, and the role of growth factor signalling in AR activation. 3. Identify androgen-regulated genes in CW22 and determine their expression levels in CWR22R. A closely related Aim 4 will further characterize the mutant AR (H874Y) which is expressed in CWR22 and has an altered steroid binding specificity. Activation of the mutant AR by dihydrotestosterone is normal in transcription assays but response to the adrenal-derived dehydroepiandrosterone (DHEA) is greater than wild-type AR. We will determine relative responsiveness of CWR22 and CWR22R to testicular androgens and the ability of this mutant AR to mediate gene activation and growth effects of DHEA. It is expected that this research will delineate the role of AR and contribute to a better understanding of gene regulation and growth in recurrent CaP.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
1P01CA077739-01
Application #
6103478
Study Section
Project Start
1998-08-01
Project End
1999-07-31
Budget Start
1997-10-01
Budget End
1998-09-30
Support Year
1
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Type
DUNS #
078861598
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Li, Qiuhui; Deng, Qu; Chao, Hsueh-Ping et al. (2018) Linking prostate cancer cell AR heterogeneity to distinct castration and enzalutamide responses. Nat Commun 9:3600
Fiandalo, Michael V; Wilton, John H; Mantione, Krystin M et al. (2018) Serum-free complete medium, an alternative medium to mimic androgen deprivation in human prostate cancer cell line models. Prostate 78:213-221
Askew, Emily B; Bai, Suxia; Parris, Amanda B et al. (2017) Androgen receptor regulation by histone methyltransferase Suppressor of variegation 3-9 homolog 2 and Melanoma antigen-A11. Mol Cell Endocrinol 443:42-51
Komisarof, Justin; McCall, Matthew; Newman, Laurel et al. (2017) A four gene signature predictive of recurrent prostate cancer. Oncotarget 8:3430-3440
Su, Shifeng; Chen, Xiaoyu; Geng, Jiang et al. (2017) Melanoma antigen-A11 regulates substrate-specificity of Skp2-mediated protein degradation. Mol Cell Endocrinol 439:1-9
Itkonen, Harri M; Brown, Michael; Urbanucci, Alfonso et al. (2017) Lipid degradation promotes prostate cancer cell survival. Oncotarget 8:38264-38275
Stocking, John J; Fiandalo, Michael V; Pop, Elena A et al. (2016) Characterization of Prostate Cancer in a Functional Eunuch. J Natl Compr Canc Netw 14:1054-60
Frasinyuk, Mykhaylo S; Mrug, Galyna P; Bondarenko, Svitlana P et al. (2016) Antineoplastic Isoflavonoids Derived from Intermediate ortho-Quinone Methides Generated from Mannich Bases. ChemMedChem 11:600-11
Minges, John T; Grossman, Gail; Zhang, Ping et al. (2015) Post-translational Down-regulation of Melanoma Antigen-A11 (MAGE-A11) by Human p14-ARF Tumor Suppressor. J Biol Chem 290:25174-87
Montecinos, Viviana P; Morales, Claudio H; Fischer, Thomas H et al. (2015) Selective targeting of bioengineered platelets to prostate cancer vasculature: new paradigm for therapeutic modalities. J Cell Mol Med 19:1530-7

Showing the most recent 10 out of 103 publications