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The Zinc Transporting Network is a Central Component of Dysregulation in Breast Cancer
Author(s) -
Chandler Paige,
Kochupurakkal Bose,
Lopez Veronica,
Alam Samina,
Soybel David,
Kelleher Shan
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.921.3
Subject(s) - metallothionein , breast cancer , phenotype , cancer research , biology , transporter , cytoplasm , basal (medicine) , cancer , zinc , microarray analysis techniques , gene expression , gene , chemistry , microbiology and biotechnology , endocrinology , biochemistry , genetics , organic chemistry , insulin
Breast cancer is classified into 3 major molecular subtypes (Luminal, HER2 and Basal), which differ in prognosis and therapeutic options. Numerous reports find that zinc (Zn) hyperaccumulates in breast tumors; however, the mechanisms responsible for Zn accumulation and the functional consequences of zinc accumulation are not understood. We tested the hypothesis that mechanisms responsible for Zn accumulation are subtype‐specific and that distinct patterns of sub‐cellular Zn distribution reflect the malignant phenotype of the cancer. Microarray gene expression revealed a subtype‐dependent pattern of Zn transporter expression in human breast tumors and cancer cell lines. Breast cancer cells accumulated significantly more Zn (p<0.05) than nonmalignant cells. Protein profiling of all 24 Zn transporters revealed that T47D luminal cells (LC) had greater expression of vesicular Zn importers and more vesicularized Zn pools, while MDA‐MB‐231 basal cells (BC) overexpressed the cytoplasmic Zn binding protein metallothionein. A primary difference was that LCs overexpressed the key Zn transporter ZnT2 and hyperaccumulated 2.5‐fold more Zn than BCs which did not express ZnT2. ZnT2 overexpression in MDA‐MB‐231 cells accumulated Zn in vesicles, altered morphology, arrested cells in G 1 of the cell cycle and reduced invasion by ~80%. Zn accumulation in breast tumors is due to subtype‐specific alterations in the Zn transporting network. This suggests that these alterations may underlie differences in the malignant phenotype observed in certain breast cancer subtypes.