Abstract 2420: Role of epigenetic modifications in RON/MSP induced breast cancer metastasis

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Breast cancer begins as a localized disease, but can spread to other sites within the body. This process, known as metastasis, accounts for about 90% of breast cancer deaths. Despite the central importance of metastasis in the clinical management of breast cancer, mechanisms of metastasis are still not understood. This is an area of urgent need; once breast cancer metastasizes there is no cure, and there are currently no therapies that prevent metastasis. Recent studies have revealed the importance of epigenetics in tumor initiation and progression. Epigenetic changes result from chemical modifications to DNA and/or histone proteins, which form a complex regulatory network that modulates chromatin structure and genome function. Cells may acquire an epigenotype that (1) permits their dissemination from the primary tumor mass and (2) gives the ability to survive and proliferate at a secondary tissue site. A major challenge in the breasts cancer metastasis field is the scarcity of model systems in which to study metastasis from primary tumors. Our lab discovered a role for macrophage stimulating protein (MSP) in metastasis of breast cancer, and developed a unique mouse model that showed a causal role for MSP in metastasis. MSP-expressing tumors exhibited remarkable spontaneous metastasis to many organs relevant to human breast cancer including bone, lungs, lymphatics, and liver. Indeed, we found that coordinate expression of MSP, its activating protease matriptase and its receptor RON is a significant independent prognostic factor for metastasis and poor survival in breast cancer patients. Our unpublished data revealed that, in breast cancer patients who died from metastatic disease, MSP/Ron activity correlated with upregulation of a significant number of genes that are controlled through epigenetic regulation. These data provided the first hint that MSP/Ron might promote breast cancer metastasis either directly or indirectly through epigenetic alterations. To investigate this potential function of MSP/Ron, we induced activation of the MSP/Ron pathway in MCF7 cells. Importantly, this was sufficient to confer spontaneous metastasis from tumors (arising from cells transplanted into mammary glands) to lung, liver and bone, while parental MCF7 tumors did not metastasize. Along with the prominent effect on metastasis, we found that MSP/Ron promoted (1) considerable changes in the DNA methylation profile of MCF7 cells, (2) altered expression of many genes that are thought to be involved in metastasis (3) upregulation of components of the putative DNA demethylase complex. Furthermore, metastatic cells expressing MSP/Ron from different models (cell line and primary tumors) share a number of hypomethylated/upregulated genes involved in metastasis which are exciting candidates for critical MSP/Ron effectors in metastasis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2420. doi:10.1158/1538-7445.AM2011-2420