Association of Metallothionein Overexpression with Poor Prognosis in Breast Cancer

Donald Sens, Ph.D.M
West Virginia University
R55ES10039

Background: Metallothioneins are intracellular proteins that bind metals. There are four classes of these proteins, designated MT1- MT4, that have small differences in their charge characteristics and amino acid sequences. MT1 and MT2 have been studied extensively, are found in most cells in the body, and are involved in homeostasis of zinc and copper during growth and development as well as the detoxification of cadmium and mercury. In contrast, MT3is unique in that it is mostly found in nervous tissue. MT3 also possesses a unique sequence of 8 additional amino acids that are not found in any other metallothionein protein. This sequence enabled other scientists to develop an antibody specific for MT3 which has used to study the expression of the protein in many tissues. Although MT3 is not found in normal bladder or prostate tissue, it is routinely found in tumors from these organs. The purpose of the current studies was to determine whether MT3 expression occurs in breast cancer and if it could be used as a marker for the disease.

Advance: As in the case of normal bladder and prostate tissue, MT3 expression could not be detected in normal breast tissue. However, in 25 of 34 cases of breast cancer, MT3 was expressed. The MT3 staining was localized to the cytoplasm of tumor cells in all cases of positive staining. When the 34 breast cancer cases were divided into good and bad outcomes (disease free after 5 years vs. recurrence within 5 years) and reanalyzed for MT3 staining, a trend for increase MT3 staining was apparent.

Implication: These studies demonstrate that MT3 is expressed in some breast cancer and that this expression is associated with poor outcomes. This finding may have implications for the treatment and causes of these tumors. Patients whose tumors test positive for MT3 may opt for more aggressive treatment protocols. The recent finding that MT3 remains undegraded in zinc deficient environments might enhance the possibility that MT3 expression could result in a cellular environment in which p53 and other zinc-dependent factors could be deprived of zinc. The expression of MT3 in tumors may cause a zinc-limiting cellular environment that favors tumor development.

Publication: Sens MA, Somji S, Garrett SH, Beall CL, Sens DA. Metallothionein isoform 3 overexpression is associated with breast cancers having a poor prognosis. Am J Pathol. 2001 Jul;159(1):21-6.