Research Interests
Research is focused on the role of the androgen receptor (AR) and androgen regulated genes in the recurrent growth of prostate cancer. The growth of most prostate cancers is dependent on androgen stimulation. Prostate tumors regress following androgen deprivation therapy, but growth eventually recurs in the absence of testicular androgen.

Recent studies on an androgen-dependent prostate cancer xenograft, CWR22, indicate a link between the androgen receptor and recurrent growth of prostate cancer. We found that the expression of insulin-like growth factor binding protein-5 (IGFBP-5) is
androgen-dependent in CWR22. This is of importance because IGFBP-5 has been shown to enhance the activity of IGF-1, a major factor in the growth of prostate cancer. CWR22 tumors regress following withdrawal of androgen stimulation but relapse after several months in the absence of testicular androgen. In addition to IGFBP-5, we identified several other mRNAs that are upregulated by androgen in the androgen-dependent tumor. Expression of these mRNAs decreased following androgen withdrawal but increased in the recurrent tumor despite the absence of testicular androgen. These findings suggest that androgen-independent growth of prostate cancer is similar to androgen-dependent growth in that it is driven by a network of androgen-regulated genes. Since the AR is expressed at a high level in the recurrent tumor, androgen-regulated genes in the recurrent tumor may be controlled by reactivation of the AR at a low level of androgen. Current studies are focused on factors that could mediate ligand-independent reactivation of AR or increase AR sensitivity to activation by adrenal androgens. Among the possible factors are AR coactivators, some of which may have increased activity in recurrent prostate cancer. We discovered recently that the coactivator transcriptional intermediary factor 2 (TIF2) is expressed at an increased level in a high percentage of recurrent prostate cancers. Moreover, TIF2 was shown to increase AR transactivation at physiological levels of adrenal androgens. The result suggests that coactivator overexpression in recurrent prostate cancer can maintain AR transactivation in the absence of testicular androgen.

Publications
Tan J-A, Sharief Y, Hamil KG, Gregory CW, Zang D-Y, Sar M, Gumerlock PH, deVere White RW, Pretlow TG, Harris SE, Wilson EM, Mohler JL, French FS (1997) Dehydroepiandrosterone activates mutant androgen receptors expressed in the androgen dependent human prostate cancer xenograft CWR22 and LNCaP cells. Mol Endocrinol, 11: 450-459.

Gregory CW, Hamil KC, Kim D, Hall SH, Pretlow TG, Mohler JL, French FS (1998) Androgen receptor expression in androgen-independent prostate cancer is associated with increased expression of androgen-regulated genes. Cancer Research 58: 5718-5724.

Gregory CW, Kim D, Ping Y, D'Ercole AJ, Pretlow TG, Mohler, JL, French FS (1999) Androgen receptor up-regulates insulin-like growth factor bindingprotein-5 (IGFBP-5) expression in a human prostate cancer xenograft. Endocrinology 140: 2372-2381,

Tan J-A, Hall SH, Hamil DG, Grossman GH, Petrusz P, Liao J, Shuai K, French FS (2000) Protein inhibitor of activated STAT-1 is a nuclear receptor co-regulator expressed in human testis. Mol Endocrinol, 14: 14-26

Tan J-A, Hall SH, Petrusz P, French FS (2000) Thyroid receptor activator molecule TRAM-1 is an androgen receptor coactivator. Endocrinology 141: 3440-3450.

Gross M, Liu B, Tan J-A, French FS, Carey M, Shuai K (2001) Distinct effects of PIAS proteins on androgen-mediated gene activation in prostate cancer cells. Oncogene 20: 3880-3887.

Gregory CW, Johnson RT, Mohler JL, French FS, Wilson EM. (2001) Androgen receptor stabilization in prostate cancer is associated with hypersensitivity to low androgen. Cancer Research 61: 2892-2898.

Gregory CW, Johnson RT, Presnell SC, Mohler JL, French FS (2001) Androgen receptor regulation of G1 cyclin and cyclin-dependent kinase function in the CWR22 human prostate cancer xenograft. J of Andrology 22: 537-548

Gregory CW, Bin H, Johnson RT, Ford H, Mohler JL, French FS, Wilson EM (2001) A mechanism for androgen receptor-mediated prostate cancer recurrence after androgen deprivation therapy. Cancer Research 61: 4315-4319.

Tan J-A, Hall SH, Hamil KG, Grossman G, Petrusz P, French F (2002) Protein inhibitors of activated STAT resemble scaffold attachment factors and function as interacting nuclear receptor coregulators. J Biol Chem 2777: 16993-17001

Gregory CW, Fei X, Ponguta LA, He B, Bill HM, French FS, Wilson EM (2004) Epidermal growth factor increases coactivation of the androgen receptor in recurrent prostate cancer.J Biol Chem
279:7119-7130

Mohler JL, Gregory CW, Ford HO III, Kim D, Weaver CM, Petrusz P, Wilson EM, French FS (2004) The androgen axis in recurrent prostate cancer. Clinical Cancer Res 10: 440-448

E-mail: fsfrench@med.unc.edu
Telephone: (919) 966-0930
FAX: (919) 966-2203
Address: 382 Med Sci Res Bldg, CB# 7500 Chapel Hill, NC
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