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Merck Scholar - Summer 2004 Carolina Boet
This is Carolina's second year at Southwestern University.
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RESEARCH PROJECT Effects
of DNA-Reactive a-Hydroxytamoxifen on Endometrial Cell Lines The antiestrogen tamoxifen is widely used for the treatment of breast cancer; however, its use increases the risk of endometrial cancer. Tamoxifen could exert its agonist activity through binding to the estrogen receptor (ER) or, once metabolized, through the formation of covalent DNA adducts. The objective of this research is to determine if cellular proliferation is induced by a DNA-reactive metabolite, a-hydroxy-tamoxifen (a-OH TAM), and if it is mediated through its ability to bind to the ER resulting in an activated transcription factor and/or by forming DNA adducts. We plan to screen a panel of ER-responsive genes in cultured cells beginning with insulin growth factor 1, growth hormone, Estrogen receptor (ER) and progesterone receptor because of their demonstrated up-regulation in response to estrogen agonists. [1]To determine if a-OH TAM has agonistic activity, we will measure endometrial cell proliferation, ERa and ERb protein levels using a Western blot analysis, and mRNA levels of the estrogen regulated genes using Northern blot analysis. To address how a-OH TAM regulates the expression of estrogen responsive genes, we will characterize the important determinants required for transcriptional activation using an in vitro system from a nuclear extract depleted of ER. These studies will reveal if transcriptional activity requires the ER, and if it does, if DNA binding by the ligand-ER complex is necessary. [1] Denis Stygar, Natalia Muravitskaya, Britt Eriksson, Håkan Eriksson and Lena Sahlin, Reproductive Biology and Endocrinology 1, 2-8 (2003)
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