TabBO: A model reflecting common molecular features of androgen-independent prostate cancer

We established two human prostate cancer cell lines, MDA PCa 2a and MDA PCa 2b, the TabBO model system, that reflect common features of human androgen -independent prostate cancer that are not present in other model systems: b one origin, prostate-specific antigen production, androgen receptor express ion, and androgen sensitivity. We therefore hypothesized that molecular pat hways in our model system reflect common alterations responsible for the pr ogression of a subset of human prostate cancer. Progression to androgen ind ependence has been hypothesized to be largely associated with impairment of the regulation of cell growth or apoptosis of prostate cancer cells. There fore, in this study, we examined molecular markers known or suspected to be important in prostate cancer progression and key regulators of cell growth and apoptosis: p53, p21(WAF1/CIP1), Bcl-2, Bar, retinoblastoma (Rb), and p 16(INK4A)/MTS1. We analyzed the expression of these markers in the cell lin es, their tumor of origin, and tumors derived from the cell lines by s.c. i noculation into nude mice. DNA sequencing of the entire open reading frames of the p53 and p21 genes revealed no mutations. Additionally, accumulation of the p53 protein was not found by Western blot analysis, nor was overexp ression of the Bcl-2 oncoprotein detected. Bar expression was detected in M DA PCa 2a cells, whereas it was absent in MDA PCa 2b. Rb and p16 protein ex pression was normal as measured by both Western blot and immunochemical ana lyses. Immunohistochemical studies of p53, p21, Bcl-2, and Rb in both sampl es from the original human cancer from which the lines were derived and mou se xenografts derived from the lines revealed similar levels of protein. Th ese results are consistent with reports indicating that 40-50% of bone meta stases of prostate cancer have wild-type p53, 50-70% do not overexpress the Bcl-2 protein, and mutations in the p21 gene are rare. Therefore, we concl ude that MDA PCa 2a and MDA PCa 2b reflect molecular pathways in a common s ubset of human androgen-independent prostate cancer and that important mole cular players in apoptosis (namely, p53 and Bcl-2) seem to be intact in thi s subset of androgen independent prostate cancer. Understanding the signal- transduction pathways operating in these cell lines may help to identify th erapeutic targets for prostate cancer.