Role of growth hormone in prostate cancer: rodent models

Swanson, Steven

Abstract

Although the molecular mechanisms of prostate carcinogenesis are poorly understood, new pathways have recently been identified that affect prostate biology in ways relevant to cancer. An example is the growth hormone/insulin like growth factor-I (GH/IGF) axis that has recently been shown to affect prostate proliferation, differentiation and apoptosis. An obstacle to studying the role of the GH/IGF axis in prostate carcinogenesis is the lack of appropriate animal models in which GH signaling is disrupted in a genetic background of cancer susceptibility. Our objectives are to determine whether disruption of GH signaling renders susceptible rodent strains resistant to prostate carcinogenesis. Our hypothesis is that an active, functional GH/IGF axis is required for the development of prostate cancer.
Our first aim i s to test the susceptibility of the GH deficient Spontaneous Dwarf rat to N-methyl-N-nitrosourea (MNU) induced prostate carcinogenesis. We plan to adapt the well-established Wistar-Unilever rat model for prostate cancer to the Sprague-Dawley rat. Preliminary data by others strongly suggest that the Sprague-Dawley rat is similar to the Wistar-Unilever rat in its susceptible to MNU induced prostate cancer.
Our second aim i s to determine whether a functional GH receptor is required for carcinogenesis in mice carrying a simian virus 40 (SV4O) large T antigen (Tag) transgene. We propose to cross the GH receptor deficient Laron mouse with the C3(1)/SV40 Tag transgenic, which spontaneously develops cancers. In both rat and mouse models, we expect GH signaling. Results from these studies could provide a strong rational for developing novel therapeutics targeting the GH/IGF axis for prostate cancer treatment. Furthermore, these new genetically defined animal models could be used to address fundamental questions regarding the role of GH/IGF in prostate growth, differentiation and carcinogenesis.