Molecular Medicine

, Volume 13, Issue 7–8, pp 396–406 | Cite as

The Emerging Role of the LIV-1 Subfamily of Zinc Transporters in Breast Cancer

  • Kathryn M. Taylor
  • Helen E. Morgan
  • Kathryn Smart
  • Normawati M. Zahari
  • Sara Pumford
  • Ian O. Ellis
  • John F. R. Robertson
  • Robert I. Nicholson


Zinc transporter LIV-1 (SLC39A6) is estrogen regulated and present in increased amounts in estrogen receptor-positive breast cancer as well as in tumors that spread to the lymph nodes. The LIV-1 subfamily of ZIP zinc transporters consists of nine human sequences that share considerable homology across transmembrane domains. Many of these sequences have been shown to transport zinc and/or other ions across cell membranes. Increasingly, studies have implicated members of the LIV-1 transporter subfamily in a variety of diseases. We review these studies and report our own investigations of the role in breast cancer of the nine LIV-1 zinc transporters. We have documented the response of these transporters to estrogen and antiestrogens, and also their presence in our models of resistance to antiestrogens. Resistance to antiestrogen drugs such as tamoxifen and fulvestrant often occurs in advanced breast cancer. In these models we observed differential expression of individual LIV-1 family members, which may be related to their observed variable tissue expression. We were unable detect ZIP4, which is known to be expressed in the intestine. HKE4/SLC39A7 had elevated expression in both antiestrogen-resistant cell lines, and ZIP8 had elevated expression in fulvestrant-resistant cells. In addition, we investigated the expression of the nine LIV-1 family members in a clinical breast cancer series. Although a number of different LIV-1 family members showed some association with growth factor receptors, LIV-1 was solely associated with estrogen receptor and a variety of growth factors commonly associated with clinical breast cancer. HKE4, however, did show an association with the marker of cell proliferation Ki67 the spread of breast cancer to lymph nodes.



The authors wish to thank the Tenovus cancer charity for funding and Mrs Lynne Farrow for help with the statistical analysis.


  1. 1.
    Vallee BL, Auld DS. (1990) Zinc coordination, function, and structure of zinc enzymes and other proteins. Biochemistry 29:5647–59.CrossRefGoogle Scholar
  2. 2.
    Vallee BL, Falchuk KH. (1993) The biochemical basis of zinc physiology. Physiological Rev. 73:79–118.CrossRefGoogle Scholar
  3. 3.
    Truong-Tran AQ, Carter J, Ruffin RE, Zalewski PD. (2001) The role of zinc in Caspase activation and apoptotic cell death. Biometals 14:315–30.CrossRefGoogle Scholar
  4. 4.
    Koh JY, Suh SW, Gwag BJ, He YY, Hsu CY, Choi DW. (1996) The role of zinc in selective neuronal death after transient global cerebral ischemia. Science 272:1013–6CrossRefGoogle Scholar
  5. 5.
    Palmiter RD, Huang L. (2004) Efflux and compartmentalization of zinc by members of the SLC30 family of solute carriers. Pflugers Arch. 447:744–51.CrossRefGoogle Scholar
  6. 6.
    Eide DJ. (2004) The SLC39 family of metal ion transporters. Pflugers Arch. 447:796–800.CrossRefGoogle Scholar
  7. 7.
    Taylor KM, Nicholson RI. (2003) The LZT proteins; the new LIV-1 subfamily of ZIP zinc transporters. BBA Biomembranes 1611:16–30.CrossRefGoogle Scholar
  8. 8.
    Gaither LA, Eide DJ. (2001) Eukaryotic zinc transporters and their regulation. Biometals 14: 251–70.CrossRefGoogle Scholar
  9. 9.
    Taylor KM, Morgan HE, Johnson A, Nicholson RI. (2003) Structure-function analysis of HKE4, a member of the new LIV-1 subfamily of zinc transporters. Biochem. J. 377:131–9.CrossRefGoogle Scholar
  10. 10.
    Guerinot ML. (2000) The ZIP family of metal transporters. Biochim. Biophys. Acta. 1465:190–8.CrossRefGoogle Scholar
  11. 11.
    Dalton TP, He L, Wang B, et al. (2005) Identification of mouse SLC39A8 as the transporter responsible for cadmium-induced toxicity in the testis. Proc. Natl. Acad. Sci. USA 102: 3401–6.CrossRefGoogle Scholar
  12. 12.
    Liuzzi JP, Aydemir F, Nam H, Knutson MD, Cousins RJ. (2006) Zip14 (Slc39a14) mediates non-transferrin-bound iron uptake into cells. Proc. Natl. Acad. Sci. USA. 103:13612–7.CrossRefGoogle Scholar
  13. 13.
    Kim BE, Wang F, Dufner-Beattie J, Andrews GK, Eide DJ, Petris MJ. (2004) Zn2+-stimulated endocytosis of the mZIP4 zinc transporter regulates its location at the plasma membrane. J. Biol. Chem. 279:4523–30.CrossRefGoogle Scholar
  14. 14.
    Wang F, Kim BE, Petris MJ, Eide DJ. (2004) The mammalian Zip5 protein is a zinc transporter that localizes to the basolateral surface of polarized cells. J. Biol. Chem. 279:51433–41.CrossRefGoogle Scholar
  15. 15.
    Taylor KM, Morgan HE, Johnson A, Nicholson RI. (2003) Structure-function analysis of LIV-1, the breast cancer associated protein that belongs to a new subfamily of zinc transporters. Biochem. J. 375:51–9.CrossRefGoogle Scholar
  16. 16.
    Tominaga K, Kagata T, Johmura Y, Hishida T, Nishizuka M, Imagawa M. (2005) SLC39A14, a LZT protein, is induced in adipogenesis and transports zinc. FEBS J. 272:1590–9.CrossRefGoogle Scholar
  17. 17.
    Taylor KM, Morgan HE, Johnson A, Nicholson RI. (2005) Structure-function analysis of a novel member of the LIV-1 subfamily of zinc transporters, ZIP14. FEBS Letters 579:427–32.CrossRefGoogle Scholar
  18. 18.
    Huang L, Kirschke CP, Zhang Y, Yu YY. (2005) The ZIP7 gene (Slc39a7) encodes a zinc transporter involved in zinc homeostasis of the Golgi apparatus. J. Biol. Chem. 280:15456–63.CrossRefGoogle Scholar
  19. 19.
    Begum NA, Kobayashi M, Moriwaki Y, Matsumoto M, Toyoshima K, Seya T. (2002) Mycobacterium bovis BCG cell wall and lipopolysaccharide induce a novel gene, BIGM103, encoding a 7-TM protein: identification of a new protein family having Zn-transporter and Zn-metalloprotease signatures. Genomics. 80:630–45.CrossRefGoogle Scholar
  20. 20.
    Kumanfasrovics A, Poruk KE, Osborn KA, Ward DM, Kaplan J. (2006) YKE4 (YIL023C) encodes a bidirectional zinc transporter in the endoplasmic reticulum of Saccharomyces cerevisiae. J Biol Chem. 281:22566–74.CrossRefGoogle Scholar
  21. 21.
    Kury S, Dreno B, Bezieau S, Giraudet S, Kharfi M, Kamoun R, Moisan JP. (2002) Identification of SLC39A4, a gene involved in acrodermatitis enteropathica. Nat. Genet. 31:239–40.CrossRefGoogle Scholar
  22. 22.
    Huang ZL, Dufner-Beattie J, Andrews GK. (2006) Expression and regulation of SLC39A family zinc transporters in the developing mouse intestine. Dev. Biol. 295:571–9.CrossRefGoogle Scholar
  23. 23.
    Manning DL, Robertson JFR, Ellis IO, et al. (1994) Estrogen-regulated genes in breast-cancer: association of pliv1 with lymph-node involvement Eur. J. Cancer 30A;675.CrossRefGoogle Scholar
  24. 24.
    Manning DL, McClelland RA, Knowlden JM, et al. (1995) Differential expression of estrogen-regulated genes in breast-cancer. Acta Oncologica 34:641–6.CrossRefGoogle Scholar
  25. 25.
    Tozlu S, Girault I, Vacher S, et al. (2006) Identification of novel genes that co-cluster with estrogen receptor alpha in breast tumor biopsy specimens, using a large-scale real-time reverse transcription-PCR approach. Endocr. Relat. Cancer 13:1109–20.CrossRefGoogle Scholar
  26. 26.
    Schneider J, Ruschhaupt M, Buness A, et al. (2006) Identification and meta-analysis of a small gene expression signature for the diagnosis of estrogen receptor status in invasive ductal breast cancer. Int. J. Cancer 119:2974–9.CrossRefGoogle Scholar
  27. 27.
    Chung CH, Bernard PS, Perou CM. (2002) Molecular portraits and the family tree of cancer Nat. Genet. 32:533–40.CrossRefGoogle Scholar
  28. 28.
    Perou CM, Sorlie T, Eisen MB, et al. (2000) Molecular portraits of human breast tumours. Nature 406:747–52.CrossRefGoogle Scholar
  29. 29.
    Yamashita S, Miyagi C, Fukada T, Kagara N, Che YS, Hirano T. (2004) Zinc transporter LIVI controls epithelial-mesenchymal transition in ze-brafish gastrula organizer. Nature 429:298–302.CrossRefGoogle Scholar
  30. 30.
    Taylor KM, Hiscox S, Nicholson RI. (2004) Zinc transporter LIV-1: a link between cellular development and cancer progression. Trends Endocrinol. Metab. 15:461–3.CrossRefGoogle Scholar
  31. 31.
    Mathews WR, Ong D, Milutinovich AB, Van Doren M. (2006) Zinc transport activity of Fear of Intimacy is essential for proper gonad morphogenesis and DE-cadherin expression. Development 133:1143–53.CrossRefGoogle Scholar
  32. 32.
    Liuzzi JP, Lichten LA, Rivera S, et. al. (2005) Interleukin-6 regulates the zinc transporter Zip14 in liver and contributes to the hypozincemia of the acute-phase response. Proc. Natl. Acad. Sci. USA 102:6843–8.CrossRefGoogle Scholar
  33. 33.
    Lang CJ, Murgia C, Leong M, et al. (2006) Anti-inflammatory effects of zinc and alterations in zinc transporter mRNA in mouse models of allergic inflammation. Am. J. Physiol. Lung Cell. Mol. Physiol. In press.Google Scholar
  34. 34.
    Bly M. (2006) Examination of the zinc transporter gene, SLC39A12. Schizophr. Res. 81:321–2.CrossRefGoogle Scholar
  35. 35.
    Chowanadisai W, Kelleher SL, Lonnerdal B. (2005) Zinc deficiency is associated with increased brain zinc import and LIV-1 expression and decreased ZnT-1 expression in neonatal rats. J. Nutr. 135:1002–7.CrossRefGoogle Scholar
  36. 36.
    Wang K, Zhou B, Kuo YM, Zemansky J, Gitschier J. (2002) A novel member of a zinc transporter family is defective in acrodermatitis enteropathica. Am. J. Hum. Genet. 71:66–73.CrossRefGoogle Scholar
  37. 37.
    Wang F, Kim BE, Dufner-Beattie J, Petris MJ, Andrews G, Eide DJ. (2004) Acrodermatitis enteropathica mutations affect transport activity, localization and zinc-responsive trafficking of the mouse ZIP4 zinc transporter. Hum. Mol. Genet. 13:563–71.CrossRefGoogle Scholar
  38. 38.
    Nicholson RI, Johnston SR. (2005) Endocrine therapy: current benefits and limitations. Breast Cancer Res. Treat. 93(Suppl 1):S3–10.CrossRefGoogle Scholar
  39. 39.
    Knowlden JM, Hutcheson IR, Jones HE, et al. (2003) Elevated levels of EGFR/c-erbB2 heterodimers mediate an autocrine growth regulatory pathway in Tamoxifen-resistant MCF-7 cells. Endocrinology 144:1032–44.CrossRefGoogle Scholar
  40. 40.
    McClelland RA, Barrow D, Madden TA, et al. (2001) Enhanced epidermal growth factor receptor signaling in MCF7 breast cancer cells after long-term culture in the presence of the pure antiestrogen ICI 182,780 (Faslodex) Endocrinology 142:2776–88.CrossRefGoogle Scholar
  41. 41.
    Hiscox S, Morgan L, Green TP, Barrow D, Gee J, Nicholson RI. (2006) Elevated Src activity promotes cellular invasion and motility in tamoxifen resistant breast cancer cells. Breast Cancer Res. Treat. 97:263–74.CrossRefGoogle Scholar
  42. 42.
    Knowlden JM, Hutcheson IR, Barrow D, Gee JM, Nicholson RI. (2005) Insulin-like growth factor-I receptor signaling in tamoxifen-resistant breast cancer: a supporting role to the epidermal growth factor receptor. Endocrinology 6:4609–18.CrossRefGoogle Scholar
  43. 43.
    Hiscox S, Jordan NJ, Jiang W, Harper M, McClelland R, Smith C, Nicholson RI. (2006) Chronic exposure to fulvestrant promotes overexpression of the c-Met receptor in breast cancer cells: implications for tumor-stroma interactions. Endocr. Relat. Cancer 13:1085–99.CrossRefGoogle Scholar
  44. 44.
    Hiscox S, Morgan L, Barrow D, Dutkowski C, Wakeling A, Nicholson, RI. (2004) Tamoxifen resistance in breast cancer cells is accompanied by an enhanced motile and invasive phenotype: inhibition by gefitinib (‘Iressa’, ZD1839). Clin. Exp. Metastasis 21:201–12.CrossRefGoogle Scholar
  45. 45.
    Kuske B, Naughton C, Moore K, et. al. (2006) Endocrine therapy resistance can be associated with high estrogen receptor {alpha} (ER{alpha}) expression and reduced ER{alpha} phosphorylation in breast cancer models. Endocr. Relat. Cancer 13:1121–33.CrossRefGoogle Scholar
  46. 46.
    Taylor KM, Vichova P, Hiscox S, Nicholson RI. (2005) Zinc-dependant stimulation of Src, EGFR and IGFR signaling pathways in tamoxifen-resistant breast cancer and the role of zinc transporters. Breast Cancer Res. Treat. 94:S162Google Scholar
  47. 47.
    Gamero AM, Young HA, Wiltrout RH. (2004) Inactivation of Stat3 in tumor cells: releasing a brake on immune responses against cancer? Cancer Cell 5:111–2.CrossRefGoogle Scholar
  48. 48.
    Knowlden JM, Gee JM, Bryant S, et. al. (1997) Use of reverse transcription-polymerase chain reaction methodology to detect estrogen-regulated gene expression in small breast cancer specimens. Clin. Cancer Res. 3:2165–72.PubMedGoogle Scholar
  49. 49.
    Nicholson RI, McClelland RA, Gee JM, et al. (1994) Epidermal growth factor receptor expression in breast cancer: association with response to endocrine therapy. Breast Cancer Res. Treat. 29: 117–25.CrossRefGoogle Scholar
  50. 50.
    Snead DR, Bell JA, Dixon AR, Nicholson RI, Elston CW, Blamey RW, Ellis IO. (1993) Methodology of immunohistological detection of oestrogen receptor in human breast carcinoma in formalin-fixed, paraffin-embedded tissue: a comparison with frozen section methodology. Histopathology 23:233–8.CrossRefGoogle Scholar
  51. 51.
    van Dierendonck JH, Keijzer R, van de Velde CJ, Cornelisse CJ. (1989) Nuclear distribution of the Ki-67 antigen during the cell cycle: comparison with growth fraction in human breast cancer cells. Cancer Res. 49:2999–3006.PubMedGoogle Scholar
  52. 52.
    Knowlden JM, Gee JM, Seery LT, Farrow L, Gullick WJ, Ellis IO, Blamey RW, Robertson JF, Nicholson RI. (1998) c-erbB3 and c-erbB4 expression is a feature of the endocrine responsive phenotype in clinical breast cancer. Oncogene 17:1949–57.CrossRefGoogle Scholar

Copyright information

© Feinstein Institute for Medical Research 2007

Authors and Affiliations

  • Kathryn M. Taylor
    • 1
  • Helen E. Morgan
    • 1
  • Kathryn Smart
    • 1
  • Normawati M. Zahari
    • 1
  • Sara Pumford
    • 1
  • Ian O. Ellis
    • 2
  • John F. R. Robertson
    • 3
  • Robert I. Nicholson
    • 1
  1. 1.Tenovus Centre for Cancer Research, Welsh School of PharmacyCardiff UniversityCardiffUK
  2. 2.Department of HistopathologyUniversity of Nottingham, City HospitalNottinghamUK
  3. 3.Department of SurgeryUniversity of Nottingham, City HospitalNottinghamUK

Personalised recommendations