Contribution of Na+,HCO3--cotransport to cellular pH control in human breast cancer: a role for the breast cancer susceptibility locus NBCn1 (SLC4A7)
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Contribution of Na+,HCO3--cotransport to cellular pH control in human breast cancer : a role for the breast cancer susceptibility locus NBCn1 (SLC4A7). / Bødtkjer, Ebbe; Moreira, José; Mele, Marco; Vahl, Pernille; Wielenga, Vera T.; Christiansen, Peer Michael; Jensen, Vibeke E.D.; Pedersen, Stine Helene Falsig; Aalkjær, Christian.
In: International Journal of Cancer, Vol. 132, No. 6, 2013, p. 1288-1299.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Contribution of Na+,HCO3--cotransport to cellular pH control in human breast cancer
T2 - a role for the breast cancer susceptibility locus NBCn1 (SLC4A7)
AU - Bødtkjer, Ebbe
AU - Moreira, José
AU - Mele, Marco
AU - Vahl, Pernille
AU - Wielenga, Vera T.
AU - Christiansen, Peer Michael
AU - Jensen, Vibeke E.D.
AU - Pedersen, Stine Helene Falsig
AU - Aalkjær, Christian
N1 - Copyright © 2012 UICC.
PY - 2013
Y1 - 2013
N2 - 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) ) levels >6.6, CO(2) /HCO(3) (-) -dependent mechanisms accounted for >90% 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.
AB - 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) ) levels >6.6, CO(2) /HCO(3) (-) -dependent mechanisms accounted for >90% 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.
U2 - 10.1002/ijc.27782
DO - 10.1002/ijc.27782
M3 - Journal article
C2 - 22907202
VL - 132
SP - 1288
EP - 1299
JO - International Journal of Cancer
JF - International Journal of Cancer
SN - 0020-7136
IS - 6
ER -
ID: 41003682