Abstract 899: High fat diet induced DNA methylation at transcription factor binding region and repressed gene expression of a metastasis suppressor E-cadherin in primary site of murine metastatic breast cancer (MBC), and promoted invasion of MBC cells to lung and liver

Abstract

Abstract Breast cancer (BC) is the most prevalent type of cancer among women in the US. BC survival rate has long been compromised by metastasis. Consumption of a high fat diet (HFD) is associated with increased BC risk. However, the underlying molecular mechanisms remain inconclusive. E-cadherin (Cdh1) is a metastasis suppressor, the loss of which promotes tumor invasion. We aimed to examine the effects of a HFD containing 47% kcal from fat on metastatic breast cancer (MBC) using preclinical syngeneic mouse models. To access the dietary effect on metastatic mammary tumor, we injected MBC cells into the mammary duct of BALB/c mice. To evaluate the dietary effect on the spread of MBC from bone to lung and liver tissues, MBC cells were inoculated into tibia cavity of BALB/c mice. Growth of MBC at the injection and inoculation site, and invasion of MBC to other organs were monitored in real-time by the bioluminescence imaging (BLI) system. Three weeks post injection, animals were sacrificed and tissues samples were collected. In summary, our results showed that HFD promoted the invasion of MBC cells to lung and liver of mice. H&E staining showed that there were significantly more lung tumors in the HFD group than control group in the tibial injected animals (12.9±1.6, 8.9±1.1, P<0.05), as well as more mice with liver tumors in HFD group (7 out of 16 mice with liver tumors in HFD group, 0 out of 17 mice with liver tumors in control group). Expression of Cdh1mammary tumor of mice was decreased by HFD. Intensity of methylation at the CpG-rich promoter region, where transcription factors bind, was increased by HFD in the mammary tumor. As the first to report that HFD induced DNA methylation and decreased the expression of Cdh1 in the metastatic mammary tumor, we proposed a mechanism by which HFD enhanced the invasiveness of MBC. Having laid a base and provided clues on HFD and MBC, this study also shed light on the intriguing interactions of nutrient epigenome and BC. Future studies are needed to further extrapolate our findings into the link between diet and disease in BC patients. Citation Format: Yukun Zhang, Wendan Wang, Xujuan Yang, William G. Helferich. High fat diet induced DNA methylation at transcription factor binding region and repressed gene expression of a metastasis suppressor E-cadherin in primary site of murine metastatic breast cancer (MBC), and promoted invasion of MBC cells to lung and liver [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 899. doi:10.1158/1538-7445.AM2015-899