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.