The development of drug resistance limits the long-term usefulness of tamoxifen for the treatment and prevention of breast cancer. One form of drug resistance that has been described is tamoxifen stimulated growth. We plan to advance understanding of drug resistance mechanisms by establishing new models of resistance to a range of clinically relevant anti-estrogens. A tamoxifen resistant phenotype of the well characterized MCF-7 breast cancer cell line (ER positive, p53 wild type) has been established both in vitro and in vivo. We have also found that T47D breast cancer cells (ER positive, p53 mutant) can lose ER in vitro with estrogen deprivation but unexpectedly produce ER positive tamoxifen stimulated tumors rapidly in vivo. Since anti-estrogens can cause g1 block, apoptosis and prevent angiogenesis signaling, resistant tumors must subvert these mechanisms. We propose to address the following specific aims: 1) To establish models of anti-estrogen. 3) To determine changes in cell cycle regulation, as cells and tumors convert from anti- estrogen sensitive to anti-estrogen resistant. We hypothesize that different classes of anti-estrogens will block the cell cycle for different times but eventually the cell cycle will return to an estrogen-like pattern once anti- estrogen resistance occurs. 4) To examine the change in angiogenic signaling during the development of anti-estrogen resistance. We hypothesize that cells that develop resistance in vitro may not grow in vivo because there is no selection pressure for angiogenesis. Ultimately, an anti-estrogen-stimulated tumor must achieve a full complement of angiogenesis promoting genes. We propose that overall differences between MCF-7 and T47D cells. Although it is not possible to confirm this hypothesis with a direct comparison of different cell lines, we will address the concept with MCF-7 cells, stably transfected with E6 to remove p53. A comparison of the transplantability of tamoxifen resistant T47D, MCF-7 and MCF-7 E6 cells will confirm or refute the hypothesis that drug induced tumorigenesis is enhanced through activating angiogenic pathways. The primary goal of this project is to establish a resource of well-characterized models for a range of clinically relevant anti-estrogens in vivo as a first step to translating the results to clinical samples.
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