TUMOR SUPPRESSION AND APOPTOSIS OF HUMAN PROSTATE CARCINOMA MEDIATED BY A GENETIC-LOCUS WITHIN HUMAN-CHROMOSOME 10PTER-Q11

Prostate cancer is the second leading cause of male cancer deaths in t he United States. Yet, despite a large international effort, little is known about the molecular mechanisms that underlie this devastating d isease. Prostate secretory epithelial cells and androgen-dependent pro state carcinomas undergo apoptosis in response to androgen deprivation and, furthermore, most prostate carcinomas become androgen independen t and refractory to further therapeutic manipulations during disease p rogression. Definition of the genetic events that trigger apoptosis in the prostate could provide important insights into critical pathways in normal development as well as elucidate the perturbations of those key pathways in neoplastic transformation, We report the functional de finition of a novel genetic locus within human chromosome 10pter-q11 t hat mediates both in vivo tumor suppression and in vitro apoptosis of prostatic adenocarcinoma cells, A defined fragment of human chromosome 10 was transferred via microcell fusion into a prostate adenocarcinom a cell line. Microcell hybrids containing only the region 10pter-q11 w ere suppressed for tumorigenicity following injection of microcell hyb rids into nude mice. Furthermore, the complemented hybrids undergo pro grammed cell death in vitro via a mechanism that does not require nucl ear localization of p53. These data functionally define a novel geneti c locus, designated PAC1, for prostate adenocarcinoma 1, involved in t umor suppression of human prostate carcinoma and furthermore strongly suggest that the cell death pathway can be functionally restored in pr ostatic adenocarcinoma.