ABSTRACT
We asked whether down-regulation of GH signaling could block carcinogenesis in the Probasin/TAg rat, a model of aggressive prostate cancer. The Spontaneous Dwarf rat, which lacks GH due to a mutation (dr) in its GH gene, was crossed with the Probasin/TAg rat, which develops prostate carcinomas at 100% incidence by 15 wk of age. Progeny were heterozygous for the TAg oncogene and homozygous for either the wild-type GH gene (TAg/Gh(+/+)) or the dr mutation (TAg/Gh(dr/dr)). Prostate tumor incidence and burden were significantly reduced, and tumor latency was delayed in TAg/Gh(dr/dr) rats relative to TAg/Gh(+/+) controls. At 25 wk of age, loss of GH resulted in a 20 and 80% decrease in the area of microinvasive carcinoma in the dorsal and lateral lobes, respectively. By 52 wk of age, invasive prostate adenocarcinomas were observed in all TAg/Gh(+/+) rats, whereas the majority of TAg/Gh(dr/dr) did not develop invasive tumors. Suppression of carcinogenesis could not be attributed to alterations in prostate expression of TAg or androgen receptor or changes in serum testosterone levels. As carcinogenesis progressed in TAg/Gh(+/+) rats, prostate GHR mRNA and protein expression increased significantly, but prostate IGF-I receptor mRNA and protein levels dropped. Furthermore, serum IGF-I and prostate IGF-I levels did not change significantly over the course of carcinogenesis. These findings suggest that GH plays a dominant role in progression from latent to malignant prostate cancer driven by the powerful probasin/TAg fusion gene in rats and suggest that GH antagonists may be effective at treating human prostate cancer.
Subject(s)
Adenocarcinoma/prevention & control , Androgen-Binding Protein/metabolism , Antigens, Viral, Tumor/metabolism , Growth Hormone/genetics , Growth Hormone/metabolism , Prostatic Neoplasms/prevention & control , Signal Transduction/physiology , Adenocarcinoma/metabolism , Adenocarcinoma/pathology , Androgen-Binding Protein/genetics , Animals , Animals, Genetically Modified , Antigens, Viral, Tumor/genetics , Disease Models, Animal , Down-Regulation/genetics , Insulin-Like Growth Factor I/metabolism , Male , Mutation/genetics , Prostate/metabolism , Prostate/pathology , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/pathology , RNA, Messenger/metabolism , Rats , Rats, Sprague-Dawley , Receptor, IGF Type 1/metabolism , Receptors, Androgen/metabolism , Receptors, Somatotropin , Signal Transduction/genetics , Testosterone/bloodABSTRACT
Clinical trials and laboratory-based studies indicate that the growth hormone/insulin-like growth factor-I axis may affect the development of breast cancer. The purpose of the present investigation was to develop a genetic model of mammary cancer to test the hypothesis that downregulation of GH signaling can substantially retard mammary cancer progression. We crossed the Laron mouse, in which the gene for the GH receptor/binding protein has been disrupted, with the C3(1)/TAg mouse, which develops estrogen receptor alpha negative mammary cancers. All mice used in our experiments were heterozygous for the large T antigen (TAg) and either homozygous wild-type for GHR (Ghr+/+) or null for GHR (Ghr-/-). Compared with the TAg/Ghr+/+ mice, the TAg/Ghr-/- mice showed delayed mammary cancer latency with significantly decreased multiplicity (9.8 +/- 1.4 versus 3.2 +/- 1.2) and volume (776.1 +/- 284.4 versus 50.5 +/- 8.9 mm3). Furthermore, the frequency of mammary hyperplasias was significantly reduced in the TAg/Ghr-/- mice (15.0 +/- 1.7 versus 6.8 +/- 1.7). To establish that these mammary cancers were estrogen-independent, 12-week-old TAg/Ghr+/+ mice, which lack visible hyperplasia, were either ovariectomized (ovx) or sham operated (sham). Compared with the sham group, ovariectomy resulted in no difference in the frequency of mammary hyperplasia, mammary tumor latency, incidence, multiplicity or tumor size. Together, these data demonstrate that the disruption of GH signaling significantly retards TAg-driven mammary carcinogenesis, and suggest that disrupting GH signaling may be an effective strategy to inhibit the progression of estrogen-independent breast cancer.
Subject(s)
Antigens, Polyomavirus Transforming/physiology , Carrier Proteins/physiology , Estrogens/metabolism , Growth Hormone/metabolism , Mammary Neoplasms, Experimental/prevention & control , Signal Transduction , Animals , Antigens, Polyomavirus Transforming/genetics , Carrier Proteins/genetics , Cell Proliferation , Disease Models, Animal , Estrogen Receptor alpha/metabolism , Female , Growth Disorders/genetics , Growth Disorders/metabolism , Heterozygote , Homozygote , Hyperplasia/pathology , Hyperplasia/prevention & control , Mammary Neoplasms, Experimental/etiology , Mice , Mice, Knockout , Mice, Transgenic , Ovariectomy , Polymerase Chain ReactionABSTRACT
Considerable animal and human data have indicated that selenium is effective in reducing the incidence of several different types of cancer, including that of the prostate. However, the mechanism by which selenium inhibits carcinogenesis remains unknown. One possibility is that dietary selenium influences the levels of selenium-containing proteins, or selenoproteins. Selenoproteins contain selenium in the form of selenocysteine and perform a variety of cellular functions, including antioxidant defense. To determine whether the levels of selenoproteins can influence carcinogenesis independent of selenium intake, a unique mouse model was developed by breeding two transgenic animals: mice with reduced selenoprotein levels because of the expression of an altered selenocysteine-tRNA (i6A-) and mice that develop prostate cancer because of the targeted expression of the SV40 large T and small t oncogenes to that organ [C3(1)/Tag]. The resulting bigenic animals (i6A-/Tag) and control WT/Tag mice were assessed for the presence, degree, and progression of prostatic epithelial hyperplasia and nuclear atypia. The selenoprotein-deficient mice exhibited accelerated development of lesions associated with prostate cancer progression, implicating selenoproteins in cancer risk and development and raising the possibility that selenium prevents cancer by modulating the levels of these selenoproteins.
Subject(s)
Gene Expression Regulation, Neoplastic , Prostatic Neoplasms/diagnosis , Prostatic Neoplasms/genetics , Selenoproteins/deficiency , Animals , Disease Models, Animal , Glutathione Peroxidase/metabolism , Male , Mice , Mice, Transgenic , Neoplasm Invasiveness , Prostate/metabolism , Selenoproteins/geneticsABSTRACT
Recent epidemiological studies suggest that elevated serum titers of IGF-I, which are, to a large degree, regulated by GH, are associated with an increase in prostate cancer risk. The purpose of the current study was to develop the first animal models to directly test the hypothesis that a normal, functional GH/IGF-I axis is required for prostate cancer progression. The GH receptor (GHR) gene-disrupted mouse (Ghr(-/-)), which has less than 10% of the plasma IGF-I found in GHR wild-type mice, was crossed with the C3(1)/T antigen (Tag) mouse, which develops prostatic intraepithelial neoplasia driven by the large Tag that progress to invasive prostate carcinoma in a manner similar to the process observed in humans. Progeny of this cross were genotyped and Tag/Ghr(+/+) and Tag/Ghr(-/-) mice were killed at 9 months of age. Seven of eight Tag/Ghr(+/+) mice harbored prostatic intraepithelial neoplasia lesions of various grades. In contrast, only one of the eight Tag/Ghr(-/-) mice exhibited atypia (P < 0.01, Fischer's exact test). Disruption of the GHR gene altered neither prostate androgen receptor expression nor serum testosterone titers. Expression of the Tag oncogene was similar in the prostates of the two mouse strains. Immunohistochemistry revealed a significant decrease in prostate epithelial cell proliferation and an increase in basal apoptotic indices. These results indicate that disruption of GH signaling significantly inhibits prostate carcinogenesis.
