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. Estrogen has been shown to play a key role in the development and progression of breast cancer with 2/3 of tumors expressing estrogen receptor-α (ERα). Under prolonged exposure to endogenous estrogens, breast tumors develop. Over the past two decades, Tamoxifen has been the most effective anti-estrogen therapy in the treatment of ERα-positive breast cancer (Osbourne et al., 1998). Unfortunately, patients eventually acquire resistance to Tamoxifen within four to eight years. Previous research has shown activation of PI3K/AKT2 and Ras/MAPK signaling pathways lead to tamoxifen resistance (Atanaskova, N et al., 2002). The purpose of this project is to establish the role of the PI3K/AKT2 pathway and its downstream signaling molecules, specifically mTOR, in anti-estrogen treatment. Inhibition of mTOR signaling by rapamycin was done to determine if p70 S6 Kinase and 4E-BP1 activation could be inhibited. In turn, cell cycle progression and tumor growth would, in theory, stop; therefore, tamoxifen resistance could be reversed in tumor cells that overexpress activated AKT2. Western blot analyses were conducted to visualize phosphorylated levels of 4E-BP1 and p70 S6 Kinase in EGFR/MCF-7 and MCF-7 cells. Overall, this research has implications for improving estrogen-mediated breast cancer treatment with Tamoxifen.