The Notch developmental pathway influences cell lineage decisions by modulating differentiation, survival and proliferation during embryogenesis. Deregulation of Notch pathway in adults may enhance tumor formation by inhibition of tumor cell apoptosis, evasion of cell cycle checkpoints, and promotion of tumor growth. Even so, downstream effector molecules of Notch signaling in tumor cell maintenance have not been completely elucidated. In preliminary experiments supporting this application, we demonstrate that Notch signaling induces the expression of survivin, a cancer gene with essential functions in mitotic regulation and apoptotic inhibition, in breast cancer cells. Furthermore, preliminary data show Notch inhibition specifically reduces viability in tumor cells highlighting it as a potential anti-cancer therapeutic. The hypothesis of the present proposal is that survivin acts as a downstream effector gene of Notch activation in breast cancer thereby contributing to tumorigenesis.
The aim of the project is 1) to investigate the biochemical mechanisms of Notch-mediated survivin protein expression, 2) to characterize the functional implications for Notch-induced survivin expression with respect to cell cycle control and cell viability. ? ? The experimental plan will provide me with a broad exposure to techniques in molecular and cellular biology, encompassing methods in gene expression, cell division, and modulation of apoptosis. The ramifications of the Notch/survivin signaling axis offer a unique training mechanism to learn new techniques in promoter analysis, and cell cycle control. Lastly, this diversified experimental plan will provide many opportunities to interact and potentially collaborate with other faculty members while exploring fields of study in cellular signaling, development, and cancer biology. This multifaceted approach is ideally suited to unravel a potentially critical signaling network in breast cancer development, help build a solid experimental foundation for my future career in biomedical sciences, and offer an intricate experimental problem that will enrich my critical thinking and scientific insight. ? ? Overall, the embodied work will broaden our understanding of how developmental pathways assist tumor formation. Deciphering the cellular context in which Notch becomes oncogenic may contribute to our understanding of how tumor cells process extrinsic signals differently than normal cells. Most importantly, mechanistic details of Notch/survivin signaling can be parlayed into the development of rational innovative therapeutics to treat cancer. ? ? ?
| Lee, Connie W; Raskett, Christopher M; Prudovsky, Igor et al. (2008) Molecular dependence of estrogen receptor-negative breast cancer on a notch-survivin signaling axis. Cancer Res 68:5273-81 |
| Lee, Connie W; Simin, Karl; Liu, Qin et al. (2008) A functional Notch-survivin gene signature in basal breast cancer. Breast Cancer Res 10:R97 |
