Attenuation of Estrogen-Induced Cell Proliferation

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DESCRIPTION (provided by applicant): The long-term goal of this project is to identify a mechanism by which normal cells are able to restrain growth when stimulated by estrogen. When rats are chronically treated with estrogen, the cells of the pituitary first respond with increased cell proliferation, but then suppress proliferation after a few days. While models such as cultured cell lines and tumor abound for the study of stimulation of growth by steroids, there is a dearth of systems to investigate the subsequent suppression of growth. This growth control phenomenon will be investigated using the genetically tractable model system of the rat pituitary. Rat pituitary growth in response to chronic estrogen exposure is controlled by a group of genetic factors known as quantitative trait loci (QTL) which includes Edpm3 (estrogen-dependent pituitary mass QTL on rat Chromosome 3). The BN rat strain has growth suppressing alleles of Edpm3 and can mount the normal growth control response, even when continuously exposed to estrogen for 10 weeks. In contrast, The F344 rat strain has alleles of Edpm3 that are defective in control of steroid-dependent pituitary growth. Consequently, estrogen treatment of F344 rats induces uncontrolled cell proliferation and prolactinoma. Aim #1 of this project is to develop a primary cell culture system to investigate the effect of the BN allele of Edpm3 on estrogen-induced cell proliferation. (All work to date has been done in the animal.) Aim #2 is to test the hypothesis that the BN allele of Edpm3 attenuates a component of paracrine growth control. Aim #3 is to identify growth regulatory factors whose estrogen-dependent expression is affected by Edpm3 genotype.