The importance of targeting signalling mechanisms of the SLC39A family of zinc transporters to inhibit endocrine resistant breast cancer
Aim: Zinc is a key secondary messenger that can regulate multiple signalling pathways within cancer cells, thus its levels need to be strictly controlled. The Zrt, Irt-like protein (ZIP, SLC39A) family of zinc transporters increase cytosolic zinc from either extracellular or intracellular stores. T...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Open Exploration Publishing Inc.
2022-04-01
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| Series: | Exploration of Targeted Anti-tumor Therapy |
| Subjects: | |
| Online Access: | https://www.explorationpub.com/Journals/etat/Article/100280 |
| _version_ | 1811288391480770560 |
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| author | Samuel Jones Georgia Farr Thirayost Nimmanon Silvia Ziliotto Julia M.W. Gee Kathryn M. Taylor |
| author_facet | Samuel Jones Georgia Farr Thirayost Nimmanon Silvia Ziliotto Julia M.W. Gee Kathryn M. Taylor |
| author_sort | Samuel Jones |
| collection | DOAJ |
| description | Aim:
Zinc is a key secondary messenger that can regulate multiple signalling pathways within cancer cells, thus its levels need to be strictly controlled. The Zrt, Irt-like protein (ZIP, SLC39A) family of zinc transporters increase cytosolic zinc from either extracellular or intracellular stores. This study examines the relevance of zinc transporters ZIP7 and ZIP6 as therapeutic targets in tamoxifen resistant (TAMR) breast cancer.
Methods:
A series of in vitro assays, including immunohistochemistry, immunofluorescence, flow cytometry, and western blotting were used to evaluate levels and activity of ZIP7 and ZIP6 in models of TAMR and sensitive (MCF-7) breast cancer. Analyses of these transporters in the clinical setting were performed using publicly available online resources: Gene Expression Profiling Interactive Analysis (GEPIA)2 and Kaplan-Meier Plotter (KmPlot).
Results:
Both total and activated levels of ZIP7 were significantly elevated in TAMR cells versus responsive MCF-7 cells. This was accompanied by an associated increase in free cytoplasmic zinc leading to amplification of downstream signals. Consistent with our proposed model, activated ZIP6 levels correlated with mitotic cells, which could be efficiently inhibited through use of our anti-ZIP6 monoclonal antibody. Mitotic inhibition translated to impaired proliferation in both models, with TAMR cells displaying increased sensitivity. Analysis of matched tumour and normal breast samples from patients revealed significant increases in both ZIP7 and ZIP6 in tumours, as well as family member ZIP4. Kaplan-Meier analysis revealed that high ZIP7 levels correlated with decreased overall and relapse-free survival (RFS) of patients, including patient groups who had received systemic endocrine therapy or tamoxifen only. In contrast, high ZIP6 levels were significantly linked to improved overall and RFS in all patients, as well as RFS in patients that received systemic endocrine therapy.
Conclusions:
TAMR cells displayed increased activity of both ZIP7 and ZIP6 transporters compared to anti-hormone responsive cells, suggesting their potential as novel therapeutic targets following development of resistant disease. |
| first_indexed | 2024-04-13T03:36:30Z |
| format | Article |
| id | doaj.art-dca079b33aba4e5fa86c69cc1951f63b |
| institution | Directory Open Access Journal |
| issn | 2692-3114 |
| language | English |
| last_indexed | 2024-04-13T03:36:30Z |
| publishDate | 2022-04-01 |
| publisher | Open Exploration Publishing Inc. |
| record_format | Article |
| series | Exploration of Targeted Anti-tumor Therapy |
| spelling | doaj.art-dca079b33aba4e5fa86c69cc1951f63b2022-12-22T03:04:19ZengOpen Exploration Publishing Inc.Exploration of Targeted Anti-tumor Therapy2692-31142022-04-013222423910.37349/etat.2022.00080The importance of targeting signalling mechanisms of the SLC39A family of zinc transporters to inhibit endocrine resistant breast cancerSamuel Jones0https://orcid.org/0000-0001-9953-2952Georgia Farr1https://orcid.org/0000-0002-8931-7615Thirayost Nimmanon2https://orcid.org/0000-0001-8765-1268Silvia Ziliotto3https://orcid.org/0000-0002-7661-4477Julia M.W. Gee4https://orcid.org/0000-0001-6483-2015Kathryn M. Taylor5https://orcid.org/0000-0002-9576-9490School of Pharmacy and Pharmaceutical Sciences, Cardiff University, CF10 3NB Cardiff, UKSchool of Pharmacy and Pharmaceutical Sciences, Cardiff University, CF10 3NB Cardiff, UKDepartment of Pathology, Phramongkutklao College of Medicine, Bangkok 10400, ThailandSchool of Biosciences, Cardiff University, CF10 3AX Cardiff, UKSchool of Pharmacy and Pharmaceutical Sciences, Cardiff University, CF10 3NB Cardiff, UKSchool of Pharmacy and Pharmaceutical Sciences, Cardiff University, CF10 3NB Cardiff, UKAim: Zinc is a key secondary messenger that can regulate multiple signalling pathways within cancer cells, thus its levels need to be strictly controlled. The Zrt, Irt-like protein (ZIP, SLC39A) family of zinc transporters increase cytosolic zinc from either extracellular or intracellular stores. This study examines the relevance of zinc transporters ZIP7 and ZIP6 as therapeutic targets in tamoxifen resistant (TAMR) breast cancer. Methods: A series of in vitro assays, including immunohistochemistry, immunofluorescence, flow cytometry, and western blotting were used to evaluate levels and activity of ZIP7 and ZIP6 in models of TAMR and sensitive (MCF-7) breast cancer. Analyses of these transporters in the clinical setting were performed using publicly available online resources: Gene Expression Profiling Interactive Analysis (GEPIA)2 and Kaplan-Meier Plotter (KmPlot). Results: Both total and activated levels of ZIP7 were significantly elevated in TAMR cells versus responsive MCF-7 cells. This was accompanied by an associated increase in free cytoplasmic zinc leading to amplification of downstream signals. Consistent with our proposed model, activated ZIP6 levels correlated with mitotic cells, which could be efficiently inhibited through use of our anti-ZIP6 monoclonal antibody. Mitotic inhibition translated to impaired proliferation in both models, with TAMR cells displaying increased sensitivity. Analysis of matched tumour and normal breast samples from patients revealed significant increases in both ZIP7 and ZIP6 in tumours, as well as family member ZIP4. Kaplan-Meier analysis revealed that high ZIP7 levels correlated with decreased overall and relapse-free survival (RFS) of patients, including patient groups who had received systemic endocrine therapy or tamoxifen only. In contrast, high ZIP6 levels were significantly linked to improved overall and RFS in all patients, as well as RFS in patients that received systemic endocrine therapy. Conclusions: TAMR cells displayed increased activity of both ZIP7 and ZIP6 transporters compared to anti-hormone responsive cells, suggesting their potential as novel therapeutic targets following development of resistant disease.https://www.explorationpub.com/Journals/etat/Article/100280zinc transportslc39a7slc39a6slc39a10tamoxifen resistancestat3zip6zip7 |
| spellingShingle | Samuel Jones Georgia Farr Thirayost Nimmanon Silvia Ziliotto Julia M.W. Gee Kathryn M. Taylor The importance of targeting signalling mechanisms of the SLC39A family of zinc transporters to inhibit endocrine resistant breast cancer Exploration of Targeted Anti-tumor Therapy zinc transport slc39a7 slc39a6 slc39a10 tamoxifen resistance stat3 zip6 zip7 |
| title | The importance of targeting signalling mechanisms of the SLC39A family of zinc transporters to inhibit endocrine resistant breast cancer |
| title_full | The importance of targeting signalling mechanisms of the SLC39A family of zinc transporters to inhibit endocrine resistant breast cancer |
| title_fullStr | The importance of targeting signalling mechanisms of the SLC39A family of zinc transporters to inhibit endocrine resistant breast cancer |
| title_full_unstemmed | The importance of targeting signalling mechanisms of the SLC39A family of zinc transporters to inhibit endocrine resistant breast cancer |
| title_short | The importance of targeting signalling mechanisms of the SLC39A family of zinc transporters to inhibit endocrine resistant breast cancer |
| title_sort | importance of targeting signalling mechanisms of the slc39a family of zinc transporters to inhibit endocrine resistant breast cancer |
| topic | zinc transport slc39a7 slc39a6 slc39a10 tamoxifen resistance stat3 zip6 zip7 |
| url | https://www.explorationpub.com/Journals/etat/Article/100280 |
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