Abstract B37: PSCA haploinsufficiency enhances prostate tumor growth in prostate-specific Pten knockout mice

Abstract

Abstract Prostate cancer is a heterogeneous disease, with multiple stages of cancer evident within an individual organ. Although some of the genetic changes necessary to initiate or advance prostate cancer have been identified, in order to develop effective therapies, it is critical to understand the different means by which this disease develops and progresses. Prostate Stem Cell Antigen (PSCA) is a GPI-anchored cell surface protein that is expressed in the normal epithelial cells of a restricted set of organs, including prostate, bladder, stomach, kidney and pancreas. Over-expression of PSCA is found in all stages of prostate cancer, from PIN to metastasis. We are investigating the biological function of PSCA in prostate tumorigenesis. We recently reported that deletion of PSCA increases metastasis of TRAMP-induced prostate tumors in mice, suggesting that PSCA may function as a tumor suppressor. To determine the effect of modulating PSCA dosage in the context of another oncogenic signal implicated in human prostate cancer development, we crossed PSCA knockout mice to prostate-specific Pten knockout mice, and analyzed the animals at 30 weeks of age. Pten −/−;PSCA +/− mice developed significantly larger prostate tumors than Pten −/− mice that are wild-type for PSCA. These results also suggest that PSCA may function as a tumor suppressor. In contrast, mice with deletion of both copies of the PSCA gene (Pten −/−; PSCA −/− mice) developed tumors similar in size to Pten −/−;PSCA +/+ animals, consistent with the possibility that PSCA function may contribute to the early stages of cancer development. Together, our results suggest that modulation of PSCA gene dosage affects cancer initiation and progression, indicating a putative dual role for PSCA in epithelial cancer. Our current experiments are designed to determine the molecular mechanism of PSCA function. Citation Information: Cancer Res 2009;69(23 Suppl):B37.