Endocrine Regulation of Hepatocellular Carcinogenesis

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DESCRIPTION (provided by applicant): Hepatocellular carcinoma (HCC) is mainly a male disease; incidence in both men and women has increased dramatically over the past 20 yrs. Evidence indicates that estrogens protect against HCC while androgens promote it. The infant mouse treated with diethylnitrosamine (DEN) serves as a model to study these hormonal influences. Although the liver expresses estrogen receptor (ERa), the protective effects of estrogen may be mediated through prolactin (PRL); whether liver ERa or PRL receptor (PRLR) is required for the protective effect is not known. It is also unknown if liver androgen receptor (AR) is essential for androgen promotion of HCC in males. The long term goals are to determine the molecular mechanisms accounting for gender differences in HCC and to determine if environmental contaminants impinge on those mechanisms. The aims of this exploratory investigation are: 1) Determine the role of hepatic hormone receptors in modulation of liver carcinogenesis. The working hypothesis is that ERa and AR regulate expression of genes, cell proliferation and apoptosis, thereby inhibiting or promoting, respectively, tumor growth. The hypothesis will be tested using wildtype and receptor knockout mice in tumorigenesis experiments. 2) Determine the molecular mechanisms of hormonal effects in the liver. The working hypothesis is that estrogen protection and androgen enhancement derive from opposing gene regulatory events. We will determine the genes that are reciprocally regulated in the liver by estrogen and androgen. Carcinogen-initiated HCC in the mouse shares features of pathogenesis with progressive human liver disease associated with hepatitis viruses and other risk factors that ultimately result in HCC and, therefore, mechanisms of hormonal modulation of the disease process delineated in the mouse will be relevant to the human situation. These studies will also lay the basis for future investigations into the potential for endocrine disruption of the gender differences in hepatocellular carcinogenesis. Furthermore, the gene products identified may yield new biomarkers useful in predicting exposure to endocrine disrupter chemicals and other environmental chemicals that have deleterious effects in the liver.