Metallothionein 2A expression is associated with cell proliferation in breast cancer

Abstract

Metallothioneins (MTs) belong to a family of cysteine-rich, metal-binding intracellular proteins, which have been linked with cell proliferation. In this study, expression levels of the 8 known MT-1 and MT-2 functional isoforms in human invasive ductal breast cancer specimens were determined by RT-PCR. The expression profiles of the MT protein and MT-2A mRNA were further evaluated in 79 cases of human invasive ductal breast carcinoma by immunohistochemistry and in situ hybridization, and correlated with cancer cell proliferation (determined by Ki-67 nuclear antigen immunolabeling). MT-1A, MT-1E, MT-1F, MT-1G, MT-1H, MT-1X and MT-2A but not MT-1B, were detected in breast cancer tissue samples. The MT-2A mRNA transcript was the highest among all the isoforms detected. A positive correlation was observed between MT-2A mRNA and MT protein expression with Ki-67 labeling (P = 0.0003 and P < 0.0001, respectively) but not with apoptosis (P = 0.1244 and P = 0.8189, respectively). Co-localization of the MT protein and Ki-67 nuclear antigen in breast cancer cells was demonstrated by double immunofluorescence staining. There was also significantly higher MT protein and MT-2A mRNA expression in histological grade 3 tumors than in histological grade 1 and 2 tumors. The finding that MT 2A appears to be the main isoform associated with cell proliferation in invasive ductal breast cancer tissues, may have therapeutic implications.

Gene Expression Profiling of Intrahepatic Cholangiocarcinoma

“…MT2A mRNA transcript has been reported to positively correlate with cell proliferation and histological grading of breast cancer (Jin et al, 2002). In urological malignancies, up-regulation of MT2A and down-regulation of MT1A and MT1G mRNA levels have been detected in renal cancer tissues (Nguyen et al, 2000).…”

Heavy Metal-induced Metallothionein Expression Is Regulated by Specific Protein Phosphatase 2A Complexes

“…MTs are a group of intracellular low molecular (6 -7 kDa), cysteine-rich, metal-binding proteins, acting as scavengers of toxic metal ions or reactive oxygen species. MTs have been implicated in the regulation of cell proliferation and apoptosis (11,12), suggesting a role for MTs in cell survival. MT function in heavy metal detoxification primarily depends on the high affinity binding between the heavy metals and MTs, leading to the sequestration of metals away from critical macromolecules (13,14).…”

Expression of metallothionein I/II and Ki-67 antigen in various histological types of basal cell carcinoma

“…An increase in MT expression in tumor cells correlates with expression of Ki-67 proliferation antigen and a less favorable outcome of the disease [6, 7, 14--16]. It has been shown that MT-2A isoform expression in breast cancer cells stimulates cell proliferation, but does not exert anti-apoptotic properties [17]. Moreover, a decline of MT-I/II expression is associated with a decrease of PCNA and Ki-67 expression both in sun-exposed and sun-protected skin, which may indicate its impact on cell proliferation [18].…”