Abstract 5006: Elucidating the mechanism of bile acid-induced activation of estrogen receptor β in colorectal adenocarcinoma

Abstract

In previous studies, Ursodeoxycholic Acid (UDCA) was investigated as a chemopreventive drug for the prevention of colorectal adenoma recurrence. These studies revealed that the efficacy of UDCA was gender-specific. The use of UDCA in men significantly lowered the odds of advanced lesions in men, but significantly increased the odds of advanced lesions in women, more specifically, in females who were younger, obese, or whose diet was high in fat. The gender specific role of UDCA led us to investigate this bile acids’, along with deoxycholic acid's (DCA), ability to activate the estrogen receptor in colon cancer. Estrogen receptor β (ERβ) is the predominant estrogen receptor in both normal and malignant human colon tissue, and loss of ERβ has been shown to be critical for tumor cell differentiation. Elevated concentrations of bile acids have previously been shown to promote colon cancer and growing evidence indicates that these molecules play a vital role in regulating cell signaling and gene expression. In our current studies, through western blot and qRT-PCR analysis, we have shown that DCA-treated HT-29 colorectal adenocarcinoma cells significantly induce the phosphorylation of ERβ, as well as increase gene expression of the pS2 estrogen response element (ERE). UDCA was also shown to induce phosphorylation of ERβ, but much later than DCA. However, UDCA increases gene expression of pS2 at much earlier time points than DCA. In addition, we have also shown that when pre-treating HT-29 cells with the MEK 1/2 inhibitor, PD98059, bile acid-induced phosphorylation of ERβ is significantly reduced, along with ERE gene up-regulation. Collectively, this data suggests that bile acids are inducing the activation of ERβ through a ligand-independent mechanism via the MAPK signaling cascade. Citation Format: Jesse Trujillo. Elucidating the mechanism of bile acid-induced activation of estrogen receptor β in colorectal adenocarcinoma. [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 5006. doi:10.1158/1538-7445.AM2015-5006