Frank S. French
Cancer Cell Biology
Area of interest
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.