Illuminating the E2F Transcription Factors Control of Breast Cancer Metastasis

描述(申请人提供)：在人类乳腺癌中，致死的主要原因是肿瘤细胞向远处器官的转移。正因为如此，目前的研究已经揭示了许多促进远处转移的分子特征，但我们对调控转移的回路缺乏完整的了解。最近，我通过对小鼠乳腺肿瘤和人乳腺肿瘤的基因表达分析，预测了E2F在乳腺癌转移中的作用。在转移性乳腺癌的MMTV-PYMT小鼠模型中的遗传证明表明，E2F1或E2F2的缺失显著减少了肺转移的存在。在许多情况下，E2F1的丢失完全阻止了转移，这从克隆形成试验检测到的明显缺乏循环中的肿瘤细胞和肺部没有转移灶来证明。此外，与E2F WT肿瘤细胞相比，注入血流中的E2F1 KO和E2F2 KO肿瘤细胞显示出显著的肺部定植能力受损。因此，确定E2F介导转移的机制特征并将其从小鼠模型推广到人类乳腺癌具有明显的临床和翻译价值。基于这些发现和目标，我制定了几个目标。在目标1中，我的目标是研究E2F1和E2F2调节转移性基因转录的假说。在目标2中，我将验证E2F1和E2F2促进人乳腺癌转移的假设，以及E2F1和E2F2在上皮向间质转化中的作用。通过完成这项工作，我希望阐明E2F在人类乳腺癌转移中的作用。这项提案的结果有望推动未来专注于调控E2F转移以提高乳腺癌患者存活率的研究。

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.