The Role of the PI3K/AKT2 Pathway in Anti-Estrogen Resistant Breast Cancer
Busch, Stephanie M.
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Breast cancer is one of the most common forms of cancer in women in the western world. In most cases, breast cancer is estrogen dependent, and treatment with estrogen antagonists such as Tamoxifen, Fulvestrant, and Raloxifen has contributed to a significant reduction in breast cancer mortality. The anti-estrogen, Tamoxifen, competes with estrogen for binding to the estrogen receptor a. and antagonizes its mitogenic action. However, most responsive tumors will eventually acquire resistance to Tamoxifen treatment. Development of resistance against anti-estrogen treatment is a serious problem in human breast cancer therapy. An understanding of the mechanism(s) leading to tamoxifen resistance would significantly improve breast cancer treatment options. Previous data from our laboratory have shown activation of PI3K/AKT2 and Ras/MAPK signaling pathways lead to tamoxifen resistance. However, the specific role of each pathway in the development of tamoxifen resistance has yet to be determined. The purpose of this project is to establish the role of the PI3K/AKT2 pathway in breast cancer progression and its effect on anti-estrogen treatment. Signaling through the PI3K/AKT2 pathway was blocked by inhibiting mammalian target of rapamycin (mTOR). Western blot analysis indicated that rapamycin inhibited the ability of mTOR to activate translation initiation proteins including p70 S6 Kinase and 4E-BPI within EGFR transfected MCF-7 cells. Future studies will determine if inhibition of mTOR activity with rapamycin reverses tamoxifen resistance.