LIV-1 and Zn Transporters: Establishing a Link Between Hyperprolactinemia and Breast Cancer

摘要

Evidence implicates dysregulated cellular zinc (Zn) metabolism in breast cancer. Regulation of Zn transport controls programmed cell death which is uncoupled in cancer. A relationship between hyperprolactinemia and breast cancer has been observed. We speculate prolactin modulates cellular Zn metabolism. Clinical studies have suggested the Zn importer Zip6 (LIV-1) as a prognostic marker for breast cancer; however, the functional relevance is unknown. We explored Zip6 function and examined its regulation by prolactin in tumorigenic (T47D) cells. Zinc level of T47D cells was 20% higher than in normal breast cells. Zip6 protein abundance was approximately 10-fold higher, approximately 90% of which was located intracellularly, suggesting that if functional, Zip6 traffics to the plasma membrane. Zip6-attenuation reduced cellular Zn level, cytochrome c release and caspase activity but preliminarily increased cell proliferation and tumorigenesis potentially from decreased E-cadherin expression. Prolactin increased Zn uptake; however, neither Zip6 expression or localization was affected, implicating other Zn transporters in this process. In summary, Zip6 over-expression may act as a 'tumor suppressor' suggesting that therapies attempting to attenuate Zip6 expression may result in enhanced proliferation and metastasis. Thus, elucidating novel prognostic markers and understanding their role in breast cancer transformation and progression is critical to developing efficacious therapies.