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

PUBLIC ABSTRACT

Several large clinical studies have recently indicated that an elevated level of the hormone prolactin (hyperprolactinemia) is associated with a 16% increase in breast cancer, similar in magnitude to the risk of breast cancer from estrogen replacement therapy. Importantly, this association is particularly strong for estrogen- and progesterone-positive breast cancers. Drugs that induce hyperprolactinemia are widely and increasingly prescribed for the treatment of a range of illnesses including Parkinson's disease, depression, schizophrenia, and numerous behavioral disorders, aggression, and self-injury in children, adolescents, and adults. In many cases, these drugs are prescribed for patients as young as 3 years of age and must be taken throughout the rest of one's life, thus potentially increasing the risk for the development of breast cancer in an enormous number of individuals. However, the relationship between hyperprolactinemia and breast cancer is not understood. Non-cancerous cells have a defined lifespan and the hallmark of a cancerous cell is its ability to avoid entering the normal process of cell death. With respect to prolactin, most studies have focused on the role that prolactin plays in regulating the normal process of cell death and how this process is impaired in cancerous cells. We propose that an unexplored role for prolactin is its potential to regulate cellular events that occur before a cell enters into the cell death process. One such avenue may be the regulation of cellular zinc trafficking as several studies have described aberrant zinc levels in cancerous breast tissue and the regulation of cell death is dependent upon tight control of cellular zinc trafficking. Cellular zinc levels are tightly controlled through the complex integration of multiple zinc transporting proteins such as LIV-1, which has been proposed to be a novel prognostic marker for breast cancer. However, there is little understanding regarding the relationship between LIV-1 function, cellular zinc trafficking, and breast cancer. The identification of LIV-1 as a prognostic marker verifies that cellular zinc trafficking is perturbed in breast carcinomas (particularly in estrogen receptor positive). Therefore, the role of prolactin in altering cellular zinc trafficking through changes in LIV-1, and the concomitant promotion of breast cancer development/progression is a unique line of investigation with the potential to yield novel innovative ideas and therapies. The first specific aim will determine the relationship between LIV-1 function and markers of the cell death pathway in non-cancerous breast cells and determine if this relationship is altered in breast cancer cells. A second specific aim will then explore effects of prolactin on LIV-1 function in non-cancerous breast cells and, once identified, determine if cancerous breast cells respond differently to prolactin treatment. Finally, an urgent demand exists for validation and, more importantly, a functional understanding of novel, predictive markers for breast cancer prognosis and therapy selection. Thus, the third specific aim will identify other zinc transporters that may be useful as prognostic markers for breast cancer. The results of these experiments will help to identify mechanisms through which hormones (other than estrogen) may facilitate breast cancer development and progression and, if successful, may lead to the identification and understanding of other novel prognostic markers of breast cancer.