Hormone induced cancers constitute one of the major classes of human cancer accounting for about one third of the cases reported in 1990. The molecular basis of cancer induction by steroid hormones is not understood. Our novel finding that estrogen can cause peroxisome proliferations specifically in the target tissue suggests a new approach to investigate hormonal carcinogenesis. We propose to investigate the molecular basis of estrogen induction of peroxisome proliferation in two target tissues, Syrian hamster kidney and duck uropygial glands, and probe the subsequent molecular events to get clues about the mechanism of tumorigenesis. We will pursue the following specific aims: 1 . Determine the time-course of peroxisome proliferation following the initiation of estrogen treatment. 2 . Elucidate the estrogen-induced changes in gene expression related to peroxisome proliferation in hamster kidney and duck uropygial gland and the molecular events in the kidney following peroxisome proliferation using probes for oncogenes, growth factors and receptors, tumor suppressors, etc., and by differential probing of subtracted libraries to seek clues to the molecular basis of tumorigenesis. 3 . Test whether the effects of steroid hormones, analogues and antagonists on tumorigenesis correlate with their peroxisome-proliferating activity in hamster kidney. 4 . Clone, characterize and sequence the peroxisome proliferator activator receptor(s) (PPAR) and related genes from hamster kidney and duck uropygial gland and seek a steroid responsive subtype of such a receptor. 5 . Test whether the cloned peroxisome proliferator-activated receptors show binding activities and associated gene expression-stimulating activities reflecting the peroxisome proliferating and tumor inducing activities of the steroid hormones, analogues and antagonists. The results could provide new insight into the mechanism by which sex hormones induce cancer in the target tissue and possibly suggest new approaches to deal with this major human health problem.
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