Because of late diagnosis and lack of effective treatments, pancreatic cancer is the 4th leading cause of cancer death in the US, with a death to incidence ratio that is nearly equal. In an effort to improve patient survival, there needs to be a focus on molecular mechanisms that confer a metastatic phenotype. The integrin α6β4 is overexpressed in pancreatic carcinoma and plays a role in cancer progression by promoting tumor invasion and metastasis as well as cell survival. We find that integrin α6β4 overexpression leads to upregulation of cancer promoting genes such as amphiregulin and epiregulin, ligands of the epidermal growth factor receptor (EGFR). The purpose of this study is to address how integrin α6β4 upregulates these ligands. We have identified large CpG islands within the amphiregulin and epiregulin promoters (-1500 to +500 bp from TSS) using CpG plot and CpG Island searcher. This provides a potential site for epigenetic modifications, which are essentially reversible, and therefore an ideal target for treatment. To test whether integrin α6β4 contributes to this regulation through DNA methylation pancreatic cancer cells expressing low levels of α6β4 were treated with DNA methyltransferase inhibitor 5-aza-2′deoxycitidine. Using Q-PCR, our results show that inhibition of DNA methyltransferase increases amphiregulin and epiregulin expression at the mRNA level. In contrast, when cells with high levels of integrin α6β4 were treated with the hypermethylating agent, S-adenosylmethionine, it leads to a decrease in amphiregulin and epiregulin expression. This implicates α6β4 as a regulator of this process allowing us insight into how this pathway might be regulated. Using ELISA, we also provide evidence that integrin α6β4 promotes increased autocrine secretion of amphiregulin after promoter demethylation. This is of particular interest to our lab because autocrine secretion of amphiregulin and epiregulin make it possible for cancer cells to both produce and respond to their own growth factors, promoting cellular invasion and metastasis. This study indicates that overexpression of integrin α6β4 in pancreatic cancer is associated with the hypomethylation of amphiregulin and epiregulin promoters, which may play an important role in the development of a malignant phenotype.

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 3134. doi:1538-7445.AM2012-3134