Cancer cells in solid tumors exhibit greatly increased dependence on acid extrusion compared to normal cells, making acid extruding transporters potential treatment targets. We previously demonstrated strong upregulation of both acid extrusion and Na⁺,HCO₃^- cotransporter NBCn1 (SLC4A7) expression in MCF-7 human breast cancer cells by a constitutively active, truncated ErbB2/HER2 receptor, ࢞NErbB2[Lauritzen et al. 2010]. Here, we address the mechanisms of NBCn1 regulation by ErbB receptors, and the in vivo relevance of NBCn1 in human breast cancer. NBCn1 upregulation in ࢞NErbB2-expressing MCF-7 cells was dependent on ERK and Src, and PI3K-Akt regulated NBCn1 expression in both ࢞NErbB2- and vector cells. NBCn1 expression was also increased by stimulation of full-length ErbB1 or ErbB3-4. Promoter deletions and luciferase reporter assays identified a ࢞NErbB2 responsive region upstream of SLC4A7 and several relevant transcription factor (TF) binding sites. Of these TFs, Sp1 and Sp3 activity was increased by ࢞NErbB2, and overexpression of their dominant-negative forms decreased NBCn1 expression. Using matched sets of patient tissue, we showed that NBCn1 is upregulated in primary breast carcinomas and lymph node metastases compared to normal breast, and demonstrated that Na+,HCO3- cotransport is a major determinant of pHi regulation in freshly dissected human breast tumors[Boedtkjer et al. 2012]. In conclusion, we identified an NBCn1 promoter, characterized its regulation by ErbB2, and demonstrated the relevance of NBCn1 as a potential target in human breast cancer diagnosis and/or treatment.

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[1] Boedtkjer et al. 2012 Int J Cancer, in revision; [2] Lauritzen et al. 2010 Exp Cell Res 316, 2538–2553.