Abstract 1074: Genome-wide analysis of FOXM1 binding and involvement of FOXM1 in cancer stem cell and metastasis properties of endocrine-sensitive and resistant breast cancer cells.

Abstract

Abstract FOXM1 is a transcription factor that coordinates expression of late cell cycle-related genes. Elevated expression of FOXM1 in breast cancer correlates with a more aggressive tumor phenotype and, as we have previously shown, is associated with resistance to endocrine treatment via 14-3-3ζ protein signaling (Bergamaschi A. et al. Breast Cancer Research 2011, 13:R7). To better understand the role that FOXM1 plays in endocrine resistance and aggressiveness we analyzed its genome-wide DNA binding and effects on gene expression. We mapped genome-wide FOXM1 binding events, by chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq), in hormone-sensitive and resistant breast cancer cell lines after estrogen or tamoxifen treatments. We also investigated the relationship between FOXM1, estrogen receptor-α and MAPK chromatin binding events by clustering analysis of Chip-seq data and identified specific clusters of colocalized binding events as identifiers for different functional gene classes. Clusters enriched in colocalized factor binding sites were associated with genes involved in maintenance of stem cell properties and genes involved in invasion and metastasis (Rho-GTPases). Binding profiles were also integrated with expression data from FOXM1 knockdown experiments, to reveal specific FOXM1 transcriptional networks. Cell studies showed the relevance of FOXM1 in breast cancer endocrine resistance and development of metastasis. We modulated the levels of FOXM1 and some newly discovered FOXM1 regulated genes in MCF7 cells and assessed their roles in hormone resistance and breast cancer aggressiveness by several functional studies. Increased expression levels of FOXM1 were associated with an increase in the cancer stem cell population. Moreover, FOXM1 overexpressing cell lines exhibited invadopodia which correlated with an increased invasion potential. The use of a specific and selective FOXM1 inhibitor proved to be especially effective in restoring endocrine sensitivity and in decreasing breast cancer aggressiveness. Collectively, our findings define FOXM1 as a master regulator of Rho-GTPase and stem cell marker expression. Dysregulation of the FOXM1 pathway promotes breast cancer progression and therefore makes FOXM1 a relevant therapeutic target to be considered for reducing invasiveness and enhancing response to endocrine and other therapies. Supported by Department of Defense grant W81XWH-09-1-0398 and a grant from The Breast Cancer Research Foundation). Citation Format: Anna Bergamaschi, Zeynep Madak-Erdogan, Hailing Lu, Benita S. Katzenellenbogen. Genome-wide analysis of FOXM1 binding and involvement of FOXM1 in cancer stem cell and metastasis properties of endocrine-sensitive and resistant breast cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1074. doi:10.1158/1538-7445.AM2013-1074