Contribution of Na+,HCO3−-cotransport to cellular pH control in human breast cancer: A role for the breast cancer susceptibility locus NBCn1 (SLC4A7)
| Autor: | Ebbe Boedtkjer, Peer Christiansen, José M.A. Moreira, Stine F. Pedersen, Marco Mele, Pernille Vahl, Vibeke Jensen, Christian Aalkjaer, Vera Timmermans Wielenga |
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| Rok vydání: | 2012 |
| Předmět: |
Cancer Research
medicine.medical_specialty Sodium-Hydrogen Exchangers Receptor ErbB-2 Intracellular pH Breast Neoplasms Locus (genetics) Biology Malignancy Breast cancer Downregulation and upregulation Internal medicine medicine Humans RNA Messenger Cation Transport Proteins Sodium-Hydrogen Exchanger 1 Sodium-Bicarbonate Symporters Transporter Hydrogen-Ion Concentration medicine.disease Pathophysiology Endocrinology Oncology Female Human breast |
| Zdroj: | International Journal of Cancer. 132:1288-1299 |
| ISSN: | 0020-7136 |
| Popis: | Genome-wide association studies recently linked the locus for Na(+),HCO(3)(-)-cotransporter NBCn1 (SLC4A7) to breast cancer susceptibility, yet functional insights have been lacking. To determine whether NBCn1, by transporting HCO(3)(-) into cells, may dispose of acid produced during high metabolic activity, we studied the expression of NBCn1 and the functional impact of Na(+),HCO(3)(-)-cotransport in human breast cancer. We found that the plasmalemmal density of NBCn1 was 20-30% higher in primary breast carcinomas and metastases compared to matched normal breast tissue. The increase in NBCn1 density was similar in magnitude to that observed for Na(+)/H(+)-exchanger NHE1 (SLC9A1), a transporter previously implicated in cell migration, proliferation and malignancy. In primary breast carcinomas, the apparent molecular weight for NBCn1 was increased compared to normal tissue. Using pH-sensitive fluorophores, we showed that Na(+),HCO(3)(-)-cotransport is the predominant mechanism of acid extrusion and is inhibited 34 ± 9% by 200 μM 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid in human primary breast carcinomas. At intracellular pH (pH(i) ) levels6.6, CO(2)/HCO(3)(-)-dependent mechanisms accounted for90% of total net acid extrusion. Na(+)/H(+)-exchange activity was prominent only at lower pH(i) -values. Furthermore, steady-state pH(i) was 0.35 ± 0.06 units lower in the absence than in the presence of CO(2)/HCO(3)(-). In conclusion, expression of NBCn1 is upregulated in human primary breast carcinomas and metastases compared to normal breast tissue. Na(+),HCO(3)(-)-cotransport is a major determinant of pH(i) in breast cancer and the modest DIDS-sensitivity is consistent with NBCn1 being predominantly responsible. Hence, our results suggest a major pathophysiological role for NBCn1 that may be clinically relevant. |
| Databáze: | OpenAIRE |
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