Department of Biomedicine, Aarhus University, Aarhus, Denmark.
Department of Pathology, Regionshospitalet Randers, Randers, Denmark.
Elife. 2021 Jul 5;10:e68447. doi: 10.7554/eLife.68447.
Breast cancer heterogeneity in histology and molecular subtype influences metabolic and proliferative activity and hence the acid load on cancer cells. We hypothesized that acid-base transporters and intracellular pH (pH) dynamics contribute inter-individual variability in breast cancer aggressiveness and prognosis. We show that Na,HCO cotransport and Na/H exchange dominate cellular net acid extrusion in human breast carcinomas. Na/H exchange elevates pH preferentially in estrogen receptor-negative breast carcinomas, whereas Na,HCO cotransport raises pH more in invasive lobular than ductal breast carcinomas and in higher malignancy grade breast cancer. HER2-positive breast carcinomas have elevated protein expression of Na/H exchanger NHE1/SLC9A1 and Na,HCO cotransporter NBCn1/SLC4A7. Increased dependency on Na,HCO cotransport associates with severe breast cancer: enlarged CO/HCO-dependent rises in pH predict accelerated cell proliferation, whereas enhanced CO/HCO-dependent net acid extrusion, elevated NBCn1 protein expression, and reduced NHE1 protein expression predict lymph node metastasis. Accordingly, we observe reduced survival for patients suffering from luminal A or basal-like/triple-negative breast cancer with high and/or low mRNA expression. We conclude that the molecular mechanisms of acid-base regulation depend on clinicopathological characteristics of breast cancer patients. NBCn1 expression and dependency on Na,HCO cotransport for pH regulation, measured in biopsies of human primary breast carcinomas, independently predict proliferative activity, lymph node metastasis, and patient survival.
乳腺癌在组织学和分子亚型上的异质性影响代谢和增殖活性，进而影响癌细胞的酸负荷。我们假设酸碱转运体和细胞内 pH（pH）动力学有助于个体间乳腺癌侵袭性和预后的差异。我们表明，在人乳腺癌中，Na,HCO 共转运体和 Na/H 交换主导细胞的净酸外排。Na/H 交换优先增加雌激素受体阴性乳腺癌的 pH 值，而 Na,HCO 共转运体增加浸润性小叶癌比导管癌和更高恶性程度乳腺癌的 pH 值。HER2 阳性乳腺癌中 Na/H 交换蛋白 NHE1/SLC9A1 和 Na,HCO 共转运体 NBCn1/SLC4A7 的蛋白表达升高。对 Na,HCO 共转运体的依赖性增加与严重的乳腺癌相关：CO/HCO 依赖性 pH 值升高预测细胞增殖加速，而 CO/HCO 依赖性净酸外排增加、NBCn1 蛋白表达升高和 NHE1 蛋白表达降低预测淋巴结转移。因此，我们观察到 luminal A 或基底样/三阴性乳腺癌患者的生存率降低，这些患者的 和/或 mRNA 表达水平较高。我们得出结论，酸碱调节的分子机制取决于乳腺癌患者的临床病理特征。在人原发性乳腺癌活检中测量的 NBCn1 表达和对 pH 调节的 Na,HCO 共转运体依赖性，可独立预测增殖活性、淋巴结转移和患者生存。
