Prostate cancer represents the most frequently diagnosed cancer and the second leading cause of cancer death in American men, yet research on prostate carcinogenesis has lagged significantly behind that on other carcinomas. Consequently, many basic issues regarding the processes and/or molecular factors that underlie prostate cancer initiation, progression, and metastasis remain unresolved. We will develop mouse models that accurately recapitulate early stages of prostate cancer, thereby providing insight into the fundamental processes of carcinogenesis, and assigning definitive roles for candidate molecular factors involved in normal and abnormal prostate function. Our team has provided a fundamental molecular link between prostate development and carcinogenesis through our collaborative efforts in analyzing the Nkx3.1 homeobox gene and corresponding mutant mice. We have shown that Nkx3.1 (i) is the earliest known marker of the prostate, (ii) is associated with all stages of prostate development and function, and (iii) is essential for normal prostate organogenesis. Notably, Nkx3.1 mutant mice display prostatic epithelial hyperplasia and dysplasia of increasing severity with age, modeling a pre-neoplastic condition. Furthermore, the Nkx3.1 gene product displays tumor suppressor activities when overexpressed in prostate carcinoma cells. Since the human NKX3.1 gene maps to a prostate cancer """"""""hotspot"""""""", NKX3.1 represents a candidate prostate-specific tumor suppressor gene. Our model is based on the hypothesis that loss of NKX3.1 predisposes to prostate cancer, while subsequent genetic events promote progression to overt carcinoma. Thus, Nkx3.1 mutant mice provide a excellent starting point for recapitulating the early events of prostate carcinoma, and for defining downstream genetic events in cancer progression. We will examine the interaction of Nkx3.1 with other candidate tumor suppressor genes (including Pten, Mxi1, p53, and Rb) and other developmental regulatory genes (including components of the hedgehog signaling pathway) by generating the corresponding compound mutant mice and examining their potential to develop prostate carcinoma. In addition, we have developed a unique approach to investigate the role of hormones in prostate carcinogenesis in the context of our compound mutant mouse models. Importantly, our analysis of the interactions of Nkx3.1 with other tumor suppressor genes in these mutant mouse models will be balanced by validation of their relevance for human prostate carcinogenesis, as well as analysis of their collaborative roles in normal prostate development and function. Our team is uniquely poised to execute these studies since we have combined expertise in mouse embryology, prostate biology, molecular oncology, mouse pathobiology, and comparative human and mouse histopathology. We believe that our interactions with the MMHC Consortium will greatly enhance our own research and that of other members of the Consortium, and will provide the basis for many exciting avenues of future research.
Showing the most recent 10 out of 83 publications
