Post-Transcriptional Regulation of the Na+,HCO3- -cotransporter NBCn1 (SLC4A7) by a Constitutively Active ErbB2 Receptor in MCF-7 Breast Cancer Cells

Altered pH regulation is a fundamental characteristic of cancers. Net acid production is greatly increased in tumor cells, due to a shift from oxidative phosphorylation towards glycolytic metabolism. We previously showed that the Na+, HCO3- cotransporter NBCn1 (SLC4A7) is strongly upregulated in MCF-7 breast cancer cells by Kruppel-like factor 4 (KLF4) upon expression of a truncated, constitutively active ErbB2 receptor (DNErbB2) (1). GWAS studies implicate a SNP (rs4973768) in the 3' Untranslated Region (3'UTR) of NBCn1 in breast cancer development. We tested the function of the 3'UTR in regulation of NBCn1 expression by DNErbB2 signaling, and assessed the role of SNP. The NBCn1 3'UTR, cloned upstream renilla luciferase, downregulated it's activity in MCF-7 cells, while DNErbB2 expression reversed the effect. Additionally, DNErbB2 signaling increased NBCn1 mRNA stability, when compared to control MCF-7 cells, in an Actinomycin D mRNA stability assay. Further, we indentified a region between 865 bp and 11...