Abstract
Acquired resistance to the estrogen receptor (ER) antagonist tamoxifen, is a major obstacle in treatment of breast cancer. Changes in Zn2+ accumulation and distribution are associated with tamoxifen-resistance and breast cancer progression. The Zn2+-sensing G-protein coupled receptor, ZnR/GPR39, triggers signaling leading to cell growth, but a role for this receptor in breast cancer in unknown. Using fluorescence imaging, we found Zn2+-dependent Ca2+ release, mediated by ZnR/GPR39 activity, in TAMR tamoxifen-resistant cells derived from MCF-7 cells, but not in ER-expressing MCF-7 or T47D cells. Furthermore, ZnR/GPR39 signaling was monitored in ER negative BT20, MDA-MB-453 and JIMT-1 cells. Expression of ZnR/GPR39 was increased in grade 3 human breast cancer biopsies compared to grade 2. Consistently, analysis of two breast cancer patient cohorts, GDS4057 and TCGA, indicated that in ER-negative tumors higher ZnR/GPR39 mRNA levels are associated with more aggressive tumors. Activation of ZnR/GPR39 in TAMR cells triggered MAPK, mTOR and PI3K signaling. Importantly, enhanced cell growth and invasiveness was observed in the ER negative breast cancer cells, TAMR, MDA-MB-453 and BT20 cells but not in the ER expressing MCF-7 cells. Thus, we suggest ZnR/GPR39 as a potential therapeutic target for combination treatment in breast cancer, particularly relevant in ER negative tumors.
Highlights
Zinc is an essential micronutrient, and free Zn2+ ions emerged as important cellular signaling molecules involved in cell growth and survival[14,15]
We first asked if there is Zn2+-dependent Ca2+ signaling in breast cancer cell lines, initially comparing the response of MCF-7 cells (ERα, PR positive cells that express low levels of HER2) to that of the tamoxifen resistant TAMR cell line derived from MCF-7 cells[25,43,44]
Since Fura-2 is sensitive to Zn2+, we asked if the fluorescence response monitored in TAMR cells may be triggered by Zn2+ permeation
Summary
Zinc is an essential micronutrient, and free Zn2+ ions emerged as important cellular signaling molecules involved in cell growth and survival[14,15]. Increased expression of ZIP7, concomitant with endoplasmic reticulum Zn2+ accumulation, was monitored in tamoxifen resistant cells derived from MCF-7 cells, termed TAMR22–24 These changes in ZIP7 expression were further associated with enhanced EGFR activation and breast cancer cell growth[25]. The release of vesicular Zn2+ induces robust and transient rises in its local concentrations, followed by rapid re-uptake via ZIP transporters or chelation by Zn2+ binding proteins[15]. Such transient changes in concentrations of extracellular Zn2+ induce signaling via a Zn2+-sensing, G-protein coupled receptor, ZnR/GPR3933–35. The ZnR/GPR39-dependent epithelial cell growth is mediated by the signaling pathways that are constitutive active in tamoxifen resistant breast cancer[8,42]. We hypothesized that ZnR/GPR39 may be an upstream regulator of breast cancer cell proliferation
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