Effects of inhibitors of Ras signaling on the expression of human estrogen sulfotransferase (SULT1E1) in the MCF10AT1 breast epithelial cell line

Abstract

The MCF10A cell line was derived from a patient with benign proliferative breast disease. The stable transfection of MCF10A cells with the mutant T24 c-Ha-ras oncogene led to the production of a derivative cell line MCF10AT1, which is tumorigenic in immunodeficient mice. Estrogen sulfotransferase (SULT1E1) is a major estrogen inactivating enzyme in breast tissue. Previous studies suggested that SULT1E1 is differentially expressed in MCF10A relative to MCF10AT1 cells. To determine if modulations in Ras oncoprotein activity may affect the expression of SULT1E1 in MCF10AT1 cells, pre-confluent cultures of MCF10AT1 cells were treated for 48h with inhibitors of Ras signaling. Relative to vehicle-treated controls (DMSO 0.1%), treatment with the farnesyl transferase inhibitor FTI-277 (10μM) produced a ~2.4 fold increase in SULT1E1 mRNA expression. Co-treatments with FTI (10μM) and the HMG-CoA reductase inhibitor lovastatin (at 0.3 μM, 1 μM, or 3 μM), significantly induced SULT1E1 mRNA levels by ~2.8, 2.4 and 1.3 fold, respectively, relative to vehicle-treated controls. Thus, treatment with disruptors of Ras signaling in MCF10AT1 cells, induces the expression of SULT1E1. These results have implications for SULT1E1-mediated estrogen inactivation during breast epithelial neoplastic progression. Supported by NIH Grants ES05823, S11 ES11182, and ES06639.