Abstract 5310: Regulation of metastatic breast cancer by E2F transcription factors

Abstract

Abstract Metastasis is the leading cause of mortality in breast cancer and the purpose of this study was to examine the role of the E2F transcription factors in mediating the dissemination of the primary cancer. E2F transcription factors have previously been demonstrated to play a critical role in regulation of cell cycle progression. However, in prior work we have demonstrated that gene expression signatures for the E2Fs have variable levels of activation in a heterogeneous tumor model. Using predictive bioinformatic methods to assess the probability of gene pathway activation, we have predicted variable roles for the E2Fs in key mouse models of breast cancer, including Myc, PyMT and Neu. We then genetically tested these computational predictions by interbreeding E2F knockout mice to the various transgenic tumor models. These crosses have revealed that the E2Fs have unique roles in tumor initiation and progression depending upon the oncogene driving the initial tumor. There are differential effects on tumor latency with the loss of individual E2F alleles, including decreased latency with E2F2 loss in the PyMT background but increased latency and reduced incidence in the Myc background. Moreover, we have observed key differences in tumor progression, with loss of E2Fs affecting the heterogeneity of the resulting tumors. In addition to tumor initiation, we have observed striking differences in tumor progression with loss of E2Fs increasing metastasis in the Myc model but reducing metastasis in the PyMT model. In order to determine the mechanism of action for these effects, we have undertaken a gene expression analysis from both primary tumors and the metastases. Comparison of tumor models in the various backgrounds has allowed us to generate a list of E2F target genes that have effects on metastasis. Comparison of these genes to human breast cancer has revealed that the key genes also have critical roles in metastatic human breast cancer survival. These E2F targets include genes that have previously been identified as metastasis suppressors and are being validated in this process. Taken together, this work suggests a critical role for the E2F transcription factors, not only as mediators of cell cycle but in regulating the metastatic progression of metastatic breast cancer. These data also illustrate the power of combining various genomic and gene expression analysis techniques with both mouse models and clinical data associated with gene expression analysis in human breast cancer. Using this approach we are able to predict and test for the role of critical pathways, such as the E2Fs, in the progression of breast cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5310. doi:1538-7445.AM2012-5310