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Gene-environment interactions are important determinants of cancer risk. Traditionally, gene-environment interactions are thought to contribute to tumor-suppressor-gene penetrance by facilitating or inhibiting the acquisition of additional somatic mutations required for tumorigenesis. Here, we demonstrate that a distinctive type of gene-environment interaction can occur during development to enhance the penetrance of a tumor- suppressor-gene defect in the adult. Using rats carrying a germ-line defect in the tuberous sclerosis complex 2 (Tsc-2) tumor-suppressor gene predisposed to uterine leiomyomas, we show that an early- life exposure to diethylstilbestrol during development of the uterus increased tumor-suppressor-gene penetrance from 65% to >90% and tumor multiplicity and size in genetically predisposed animals, but it failed to induce tumors in wild-type rats. This exposure was shown to impart a hormonal imprint on the developing uterine myometrium, causing an increase in expression of estrogen-responsive genes before the onset of tumors. Loss of function of the normal Tsc-2 allele remained the rate-limiting event for tumorigenesis; however, tumors that developed in exposed animals displayed an enhanced proliferative response to steroid hormones relative to tumors that developed in unexposed animals. These data suggest that exposure to environmental factors during development can permanently reprogram normal physiological tissue responses and thus lead to increased tumor-suppressor-gene penetrance in genetically susceptible individuals. [ABSTRACT FROM AUTHOR]

The von Hippel-Lindau (VHL) tumor suppressor gene plays a prominent role in the development of renal cell carcinoma (RCC) in humans. VHL functions as a ubiquitin E3 ligase, controlling the stability of hypoxia inducible factor (HIF) and tumor angiogenesis. Alterations in this tumor suppressor gene are rarely observed in spontaneous or chemically induced RCC that arise in conventional strains of rodents and Vhl knockout mice (Vhl+/-) do not develop spontaneous RCC. We tested whether Vhl knockout mice exhibited increased susceptibility to renal carcinogenesis using the well-characterized renal carcinogen streptozotocin. No differences were observed between wild-type and Vhl+/- animals in the frequency or type of renal lesions induced by 50200 mg/kg streptozotocin. Carcinogen-induced RCC that developed in Vhl heterozygotes and wild-type mice did not contain mutations in the wild-type Vhl, as determined by direct sequencing of the primary tumors. While Vhl+/- mice exhibited no increase in renal lesions in response to streptozotocin, heterozygous animals did develop vascular proliferative lesions of the liver, uterus, ovary, spleen and heart. These lesions, ranging from angiectasis to hemangiosarcoma, were most prominent in the livers of Vhl+/- mice, where they were found in high incidence and high multiplicity. Wild-type mice developed a low-frequency of liver angiectasis (715%) only at the highest doses of carcinogen used (150 and 200 mg/kg, respectively) while Vhl+/- mice exhibited angiectasis, hemangioma and hemangiosarcomas with a frequency ranging from 19 to 46% at 50200 mg/kg streptozotocin. Untreated Vhl+/- mice had a spontaneous incidence of hepatic vascular lesions of 21%. Furthermore, vascular lesions of the uterus, ovary, spleen and heart were observed only in Vhl+/- mice, with an incidence of (528%). Taken together, the data indicate that heterozygosity at the Vhl locus predisposes mice to a vascular phenotype ranging from angiectasis to hemangiosarcoma, consistent with the ability of this tumor suppressor gene to control the stability of HIF and regulate key proteins that participate in angiogenesis. [ABSTRACT FROM AUTHOR]

BACKGROUND Although uterine leiomyomas or fibroids are the most common gynecological benign tumor and greatly affect reproductive health and well-being, the pathophysiology and epidemiology of uterine leiomyomas are poorly understood. Elevated blood pressure has an independent, positive association with risk for clinically detected uterine leiomyoma. Angiotensin II (Ang II) is a key biological peptide in the renin-angiotensin system that regulates blood pressure. METHODS In this study, we investigated the potential role of Ang II (1–1000 nM) in the proliferation of rat ELT-3 leiomyoma cells in vitro. RT–PCR and western blot analysis with cell proliferation and DNA transfection assays were performed to determine the mechanism of action of Ang II. RESULTS Ang II induced ELT-3 leiomyoma cell proliferation (P 1R) and AT2R mRNA and protein was confirmed. Regarding the intracellular signaling pathway, the Ang II-induced cell proliferation was AT1R-, epidermal growth factor receptor-, extracellular-regulated kinase- and protein kinase C-dependent but was not dependent on the AT2R or phosphatidylinositol-3 kinase or JAK kinase. The AT1R blocker telmisartan, effectively repressed Ang II-induced and estradiol-induced cell proliferation (P 1R, but not AT2R, plays a role in Ang II-induced ELT-3 cell proliferation. CONCLUSIONS These experimental findings in vitro highlight the potential role of Ang II in the proliferation of leiomyoma cells. [ABSTRACT FROM AUTHOR]