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The emerging role of the LIV-1 subfamily of zinc transporters in breast cancer.

ABSTRACT: 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.

SUBMITTER: Taylor KM

PROVIDER: S-EPMC1936980 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundBreast cancer (BC) is a highly heterogeneous disease. Solute carriers (SLCs) have been involved in the tumor progression of various cancer types. This study aimed to evaluate the role of these SLC-related glutamine transporters in the prognosis of BC patients by bioinformatics analysis.MethodsThis study examined the transcription and prognostic data for glutamine-related transporters in BC from Oncomine Database, which is currently the largest oncogene microarray database platform in the world. As well as Gene Expression Profiling Interactive Analysis (GEPIA), Kaplan-Meier (K-M), and cBioPortal online resources. The Tumor Immune Estimation Resource (TIMER) and GEPIA were also used to examine the relationship between SLCs and immune cell infiltration.ResultsThe expression levels of SLC1A5, SLC3A2, SLC7A5, SLC7A8, and SLC38A1 were higher in BC tissues than normal breast tissues, but the expression level of SLC6A14 was lower. The expression levels of SLC7A5, SLC7A8, SLC6A14, and SLC38A2 were related to a later clinical tumor stage. In the K-M analyses, The K-M curves revealed that patients with high SLC1A5 expression had a poor prognosis (OS HR =1.28, 95% CI: 1.06-1.54; P=0.01). The high expression of SLC3A2 was significantly correlated with a poor prognosis (DMFS HR =1.19, 95% CI: 1.02-1.39; P=0.027). Increased SLC7A5 mRNA levels and decreased SLC7A8 mRNA levels were significantly associated with a poor prognosis in terms of OS, RFS, DMFS and PPS. The high expression of SLC6A14 was significantly correlated with a poor prognosis (PPS HR =1.35, 95% CI: 1.07-1.7; P=0.011). The high expression of SLC38A1 was correlated with a better prognosis than low expression of SLC38A1 (RFS HR =0.84, 95% CI: 0.76-0.93; P=0.00077; DMFS HR =0.78, 95% CI: 0.67-0.91; P=0.0013). The infiltration of immune cells and their marker genes were associated with SLC1A5, SLC3A2, SLC7A5, SLC7A8, SLC6A14, SLC38A1, and SLC38A2 expression. SLC7A5, SLC7A8, SLC38A1, and SLC38A2 have the potential to regulate polarization in tumor-associated macrophages.ConclusionsSLC7A5, SLC7A8, SLC38A1, and SLC38A2 may regulate the polarization of tumor-associated macrophages (TAMs). SLC1A5, SLC3A2, SLC7A5, and SLC6A14 may be promising biomarkers for the BC diagnosis and may represent potential therapeutic targets for these patients.

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The emerging role of the LIV-1 subfamily of zinc transporters in breast cancer.

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