Abstract
ZIP7, a member of the ZIP family of zinc importers, resides on the endoplasmic reticulum membrane and transports zinc from intracellular stores to the cytoplasm after activation by CK2 phosphorylation on two serine residues (S275 and S276). ZIP7 is known to be required for the growth of anti-hormone resistant breast cancer models, especially those with acquired tamoxifen resistance developed from MCF-7. Using our new pS275S276ZIP7 antibody which only recognises activated ZIP7 (pZIP7), we have demonstrated that the hyperactivation of ZIP7 is prevalent in tamoxifen-resistant breast cancer cells. This evidence suggests that pZIP7 might have potential as a biomarker of acquired resistance to such anti-hormones in breast cancer, a current unmet clinical need. In this regard, we have also developed a new immunohistochemical assay for pZIP7 which allowed pZIP7 to be tested on a small clinical series of breast cancer tissues confirming its prevalence in such tumours and relationship to a variety of clinicopathological parameters and biomarkers previously associated with endocrine resistant phenotypes, notably increased activated MAPK signalling, expression of ErbB2, CD71 and the proto-oncogene c-Fos, as well as with increased tumour grade.
Highlights
ZIP7, a member of the ZIP family of zinc importers, resides on the endoplasmic reticulum membrane and transports zinc from intracellular stores to the cytoplasm after activation by CK2 phosphorylation on two serine residues (S275 and S276)
Using our new pS275S276ZIP7 antibody which only recognises activated ZIP7, we have demonstrated that the hyperactivation of ZIP7 is prevalent in tamoxifen-resistant breast cancer cells
We have developed a new immunohistochemical assay for pS275S276ZIP7 antibody which only recognises activated ZIP7 (pZIP7) which allowed pZIP7 to be tested on a small clinical series of breast cancer tissues confirming its prevalence in such tumours and relationship to a variety of clinicopathological parameters and biomarkers previously associated with endocrine resistant phenotypes, notably increased activated MAPK signalling, expression of ErbB2, CD71 and the proto-oncogene c-Fos, as well as with increased tumour grade
Summary
Zinc cannot traverse cell membranes and relies on two families of zinc transporters, the ZnT family Metallomics monoclonal antibody which binds ZIP7 only when phosphorylated on these two serine residues[17] and have demonstrated that the mobilisation of zinc induced by the activation of ZIP7 is involved in regulating growth factor signalling of many pathways known to be responsible for aggressive cancer growth This effect is directly due to the ability of released zinc to inhibit multiple tyrosine phosphatases, especially PTP1B.18. Some patients treated with endocrine agents, including anti-oestrogens, develop resistance[27] resulting in disease relapse and cancer recurrence during treatment,[28] generating a requirement for new targets to allow additional novel therapies to control this more aggressive state With this aim, we have previously developed unique anti-hormone resistant breast cancer models, both to tamoxifen[29] and Faslodexs,[30] that aim to mimic the clinical development of acquired resistance and that can help in the discovery of new potential targets. We propose that pZIP7 is a potential indicator of anti-hormone resistance, especially tamoxifen resistance, which with further study may prove to have biomarker value for cancer patients treated with anti-hormones
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