Illuminating the E2F Transcription Factors Control of Breast Cancer Metastasis

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DESCRIPTION (provided by applicant): In human breast cancer, the major cause of lethality is the metastasis of tumor cells to distant organs. Because of this, current research has revealed many of the molecular features that promote distant metastasis, yet we lack a complete understanding of the circuitry that regulates progression to metastasis. Recently, I predicted a role for the E2Fs in breast cancer metastasis using gene expression analysis of mouse mammary tumors and human breast tumors. A genetic demonstration in the MMTV-PyMT mouse model of metastatic breast cancer demonstrated that loss of E2F1 or E2F2 significantly reduces the presence of pulmonary metastases. In many cases loss of E2F1 blocked metastasis altogether, as evidenced by an apparent a lack of circulating tumor cells detected by a colony formation assay and absence of metastatic lesions in the lungs. In addition, E2F1 KO and E2F2 KO tumor cells injected into the bloodstream show remarkably impaired ability to colonize the lungs compared to E2F WT tumor cells. As a result, there is clear clinical and translational value in determining the mechanistic features of E2F mediated metastasis and extending this demonstration from the mouse model to human breast cancer. Based on these findings and goals, I have developed several aims. In aim 1, my goal is to investigate the hypothesis that E2F1 and E2F2 regulate the transcription of genes that function in metastasis. In aim 2, I will test the hypothesis that E2F1 and E2F2 promote human breast cancer metastasis and function in epithelial to mesenchymal transition. By completing this work, I expect to illuminate the role for the E2Fs in human breast cancer metastasis. The outcome of this proposal is expected to motivate future research focused on targeting E2F regulation of metastasis to improve survival for breast cancer patients.