Steven M Swanson

Interest in investigating the role of the growth hormone (GH)/insulin-like growth factor 1 (IGF-1) axis in the initiation and progression of experimentally induced carcinomas has arisen due to several observations in the human population. First, subjects with Laron syndrome who lack GH signaling have significantly lower rates of cancer than people who have normal GH signaling. Second, epidemiologic studies have found strong associations between elevated circulating IGF-1 and the incidence of several common cancers. Third, women who bear children early in life have a dramatically reduced risk of developing breast cancer, which may be due to differences in hormone levels including GH. These observations have motivated multiple studies that have experimentally altered activity of the GH/IGF-1 axis in the context of experimental carcinoma models in mice and rats. Most of these studies have utilized carcinoma models for four organ systems that are also frequent sites of carcinomas in humans: the mammary gland, prostate gland, liver, and colon. This review focuses on these studies and describes some of the most common genetic models used to alter the activity of the GH/IGF-1 axis in experimentally induced carcinomas. A recurring theme that emerges from these studies is that manipulations that reduce the activity of GH or mediators of GH action also inhibit carcinogenesis in multiple model systems.

Background Humans with inactivating mutations in growth hormone receptor (GHR) have lower rates of cancer, including prostate cancer. Similarly, mice with inactivating Ghr mutations are protected from prostatic intraepithelial neoplasia in the C3(1)/TAg prostate cancer model. However, gaps in clinical relevance in those models persist. The current study addresses these gaps and the ongoing role of Ghr in prostate cancer using loss‐of‐function and gain‐of‐function models. Methods Conditional Ghr inactivation was achieved in the C3(1)/TAg model by employing a tamoxifen‐inducible Cre and a prostate‐specific Cre. In parallel, a transgenic GH antagonist was also used. Pathology, proliferation, and gene expression of 6‐month old mouse prostates were assessed. Analysis of The Cancer Genome Atlas data was conducted to identify GHR overexpression in a subset of human prostate cancers. Ghr overexpression was modeled in PTEN‐P2 and TRAMP‐C2 mouse prostate cancer cells using stable transfectants. The growth, proliferation, and gene expression effects of Ghr overexpression was assessed in vitro and in vivo. Results Loss‐of‐function for Ghr globally or in prostatic epithelial cells reduced proliferation and stratification of the prostatic epithelium in the C3(1)/TAg model. Genes and gene sets involved in the immune system and tumorigenesis, for example, were dysregulated upon global Ghr disruption. Analysis of The Cancer Genome Atlas revealed higher GHR expression in human prostate cancers with ERG‐fusion genes or ETV1‐fusion genes. Modeling the GHR overexpression observed in these human prostate cancers by overexpressing Ghr in mouse prostate cancer cells with mutant Pten or T‐antigen driver genes increased proliferation of prostate cancer cells in vitro and in vivo. Ghr overexpression regulated the expression of multiple genes oppositely to Ghr loss‐of‐function models. Conclusions Loss‐of‐function and gain‐of‐function Ghr models, including prostatic epithelial cell specific alterations in Ghr , altered proliferation, and gene expression. These data suggest that changes in GHR activity in human prostatic epithelial cells play a role in proliferation and gene regulation in prostate cancer, suggesting the potential for disrupting GH signaling, for example by the FDA approved GH antagonist pegvisomant, may be beneficial in treating prostate cancer.