A novel system in which to study both hormone-dependent tumor growth as well as normal growth is the estrogen induction of pituitary tumors. Prolonged treatment (1-3 months) with 17beta-estradiol (E2) or diethylstilbestrol results in the induction of pituitary tumors (hyperprolactinomas) in Fischer 344 (F344) rats whereas Sprague-Dawley derived (SD) strains are resistant to such tumors. We have conducted genetic experiments indicating that the difference in tumor susceptibility between strains was not due to a single gene trait but vas probably due to a small (2-4) number of genes. Short-term (2-4 days) treatment with estrogen increases DNA synthesis in both SD and F344 pituitaries. However, DNA synthesis declines in the SD strain after 5 or 6 additional days of estrogen treatment, whereas elevated DNA synthesis persists in the F344 strain as long as estrogen is administered. Our working hypothesis is that the difference in tumor susceptibility between the strains is due to a replication repression mechanism that functions in the SD strain to restrain estrogen-stimulated cell proliferation but is deficient in F344 pituitaries. The overall objective of this proposal is to identify specific gene product(s) that relate to estrogen-induced pituitary growth and to either susceptibility or resistance of estrogen-induced tumor formation in F344 and SD rats. Key elements in cell replication and cell cycle regulation include the cyclins, which appear to function in Gl and in the G2/M transition of the cell cycle. We propose to study estrogen regulation of pituitary Gl cyclin gene expression and determine whether cyclin gene expression fits the genetic models we have previously proposed to explain estrogen-- induced F344 tumors. These studies may be extended to known repressor genes and other essential cell cycle genes. We also propose to use subtractive hybridization to identify strain-specific gene products such as the cyclin or other genes involved in growth regulation in this hormone-dependent tumor system.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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University of Wisconsin Madison
Schools of Earth Sciences/Natur
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