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Enhanced ZnR/GPR39 Activity in Breast Cancer, an Alternative Trigger of Signaling Leading to Cell Growth

Acquired resistance to the estrogen receptor (ER) antagonist tamoxifen, is a major obstacle in treatment of breast cancer. Changes in Zn(2+) accumulation and distribution are associated with tamoxifen-resistance and breast cancer progression. The Zn(2+)-sensing G-protein coupled receptor, ZnR/GPR39,...

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Autores principales: Ventura-Bixenshpaner, Hila, Asraf, Hila, Chakraborty, Moumita, Elkabets, Moshe, Sekler, Israel, Taylor, Kathryn M., Hershfinkel, Michal
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5970167/
https://www.ncbi.nlm.nih.gov/pubmed/29802348
http://dx.doi.org/10.1038/s41598-018-26459-5
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author Ventura-Bixenshpaner, Hila
Asraf, Hila
Chakraborty, Moumita
Elkabets, Moshe
Sekler, Israel
Taylor, Kathryn M.
Hershfinkel, Michal
author_facet Ventura-Bixenshpaner, Hila
Asraf, Hila
Chakraborty, Moumita
Elkabets, Moshe
Sekler, Israel
Taylor, Kathryn M.
Hershfinkel, Michal
author_sort Ventura-Bixenshpaner, Hila
collection PubMed
description Acquired resistance to the estrogen receptor (ER) antagonist tamoxifen, is a major obstacle in treatment of breast cancer. Changes in Zn(2+) accumulation and distribution are associated with tamoxifen-resistance and breast cancer progression. The Zn(2+)-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 Zn(2+)-dependent Ca(2+) 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.
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spelling pubmed-59701672018-05-30 Enhanced ZnR/GPR39 Activity in Breast Cancer, an Alternative Trigger of Signaling Leading to Cell Growth Ventura-Bixenshpaner, Hila Asraf, Hila Chakraborty, Moumita Elkabets, Moshe Sekler, Israel Taylor, Kathryn M. Hershfinkel, Michal Sci Rep Article Acquired resistance to the estrogen receptor (ER) antagonist tamoxifen, is a major obstacle in treatment of breast cancer. Changes in Zn(2+) accumulation and distribution are associated with tamoxifen-resistance and breast cancer progression. The Zn(2+)-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 Zn(2+)-dependent Ca(2+) 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. Nature Publishing Group UK 2018-05-25 /pmc/articles/PMC5970167/ /pubmed/29802348 http://dx.doi.org/10.1038/s41598-018-26459-5 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Ventura-Bixenshpaner, Hila
Asraf, Hila
Chakraborty, Moumita
Elkabets, Moshe
Sekler, Israel
Taylor, Kathryn M.
Hershfinkel, Michal
Enhanced ZnR/GPR39 Activity in Breast Cancer, an Alternative Trigger of Signaling Leading to Cell Growth
title Enhanced ZnR/GPR39 Activity in Breast Cancer, an Alternative Trigger of Signaling Leading to Cell Growth
title_full Enhanced ZnR/GPR39 Activity in Breast Cancer, an Alternative Trigger of Signaling Leading to Cell Growth
title_fullStr Enhanced ZnR/GPR39 Activity in Breast Cancer, an Alternative Trigger of Signaling Leading to Cell Growth
title_full_unstemmed Enhanced ZnR/GPR39 Activity in Breast Cancer, an Alternative Trigger of Signaling Leading to Cell Growth
title_short Enhanced ZnR/GPR39 Activity in Breast Cancer, an Alternative Trigger of Signaling Leading to Cell Growth
title_sort enhanced znr/gpr39 activity in breast cancer, an alternative trigger of signaling leading to cell growth
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5970167/
https://www.ncbi.nlm.nih.gov/pubmed/29802348
http://dx.doi.org/10.1038/s41598-018-26459-5
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