ZnR/GPR39 upregulation of K+/Cl-cotransporter 3 in tamoxifen resistant breast cancer cells

Maayan Mero, Hila Asraf, Israel Sekler, Kathryn M. Taylor, Michal Hershfinkel

Research output: Contribution to journalArticlepeer-review

15 Scopus citations


Expression of the zinc receptor, ZnR/GPR39, is increased in higher grade breast cancer tumors and cells. Zinc, its ligand, is accumulated at larger concentrations in the tumor tissue and can therefore activate ZnR/GPR39-dependent Ca2+ signaling leading to tumor progression. The K+/Cl co-transporters (KCC), activated by intracellular signaling, enhance breast cancer cell migration and invasion. We asked if ZnR/GPR39 enhances breast cancer cell malignancy by activating KCC. Activation of ZnR/GPR39 by Zn2+ upregulated K+/Cl co-transport activity, measured using NH4 + as a surrogate to K+ while monitoring intracellular pH. Upregulation of NH4 + transport was monitored in tamoxifen resistant cells with functional ZnR/GPR39-dependent Ca2+ signaling but not in MCF-7 cells lacking this response. The NH4 + transport was Na+-independent, and we therefore focused on KCC family members. Silencing of KCC3, but not KCC4, expression abolished Zn2+-dependent K+/Cl co-transport, suggesting that KCC3 is mediating upregulated NH4 + transport. The ZnR/GPR39-dependent KCC3 activation accelerated scratch closure rate, which was abolished by inhibiting KCC transport with [(DihydroIndenyl) Oxy] Alkanoic acid (DIOA). Importantly, silencing of either ZnR/GPR39 or KCC3 attenuated Zn2+-dependent scratch closure. Thus, a novel link between KCC3 and Zn2+, via ZnR/GPR39, promotes breast cancer cell migration and proliferation.

Original languageEnglish
Pages (from-to)12-20
Number of pages9
JournalCell Calcium
StatePublished - 1 Jul 2019


  • Breast cancer
  • K/Cl co-transport
  • KCC3
  • MAPK
  • PI3K
  • Zinc signaling
  • ZnR/GPR39

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology


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