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Background: WNK kinase is a serine/threonine kinase that plays an important role in normal blood pressure homeostasis. WNK3 was previously found to enhance the activity of sodium chloride cotransporter (NCC) in Xenopus oocyte. However, the mechanism through which it works remains unclear., Methods: Using overexpression and siRNA knock-down techniques, the effects of WNK3 on NCC in both Cos-7 and mouse distal convoluted cells were analyzed by Western blot., Results: We found that WNK3 significantly increased NCC protein expression in a dose-dependent manner. NCC protein expression in Cos-7 cells was markedly decreased after 2 h treatment with protease inhibitor, cycloheximide (CHX) in the NCC alone group, but was significantly decreased after 8 h treatment of CHX in the WNK3 + NCC group. WNK3 significantly increased NCC protein expression in both NCC alone and WNK3 + NCC groups regardless the overnight treatments of bafilomycin A1, a proton pump inhibitor, suggesting that WNK3-mediated increased NCC expression is not dependent on the lysosomal pathway. We further found that WNK3 group had a quicker NCC recovery than the control group using CHX pulse assay, suggesting that WNK3 increases NCC protein synthesis. WNK3 enhanced NCC protein level while reducing ERK 1/2 phosphorylation. In addition, knock-down of ERK 1/2 expression reversed WNK3-mediated increase of NCC expression., Conclusion: These results suggest that WNK3 enhances NCC protein expression by increasing NCC synthesis via an ERK 1/2-dependent signaling pathway., (© 2016 S. Karger AG, Basel.)

Sixty patients with stage IIIA and IIIB breast cancer have been treated with a combined modality approach including induction chemotherapy, surgery and adjuvant chemotherapy: 74.5% of patients achieved an objective response after 3 cycles of induction chemotherapy, and 98.3% of patients were rendered disease-free after induction chemotherapy and surgery or radiotherapy; at 4 years, actuarial survival and disease-free survival are 71.5% and 43%, respectively. These results are significantly better than our historical control, and locally advanced breast cancer must now be considered a curable disease when treated with an aggressive multimodal approach.