Expression of metallothionein 3 in ductal breast cancer

Abstract

Metallothionein 3 (MT-3) has the ability to regulate the growth of nerve cells, but the significance of MT-3 expression outside the central nervous system and its participation in carcinogenesis have not yet been clarified. The aim of our study was to investigate the expression of MT-3 in ductal breast cancer and to determine its relationship with well-defined clinicopathological factors in this type of tumor. The study was conducted on 134 cases of invasive ductal breast carcinoma (IDC), 42 samples of non-malignant breast tissue (NMBT), and 26 cases of mastopathy. Moreover, selected breast cancer cell lines (MCF-7, SKBR-3, MDA-MB-231, BO2) and normal human breast epithelial cells (hTERT-HME1) were used. The expression of MT-3 was examined on the protein level using immunohistochemistry and on the mRNA level using real-time PCR. It was shown that the MT-3 protein in cells of IDC and mastopathy appeared in the cytoplasm as well as in the cell nuclei. Both the cytoplasmic and nuclear expression of MT-3 was significantly lower in IDC than in the mastopathies (p<0.0001 and p<0.001). However, no significant correlation was demonstrated between the level of MT-3 protein and the studied clinicopathological factors. The mRNA expression of MT-3 in IDC was also lower than in non‑malignant breast tissue (p<0.0001). Furthermore, in the cases of IDC with lymph node metastasis, the level of MT-3 mRNA was significantly lower than in the cases without metastasis (p=0.0199). The expression of MT-3 mRNA in breast cancer cell lines was significantly lower than in the normal human breast epithelial cell line (p<0.001). These results suggest that MT-3 may play a role in the malignant transformation of breast epithelial cells and in tumor progression.

The roles of metallothioneins in carcinogenesis

“…A decrease in MT3 expression was observed in pituitary adenocarcinoma with spinal cord metastasis [ 87 ]. Likewise, Gomulkiewicz et al showed that the MT3 expression was significantly lower in patients with ductal breast cancer with lymph node metastasis than in patients without metastasis [ 88 ]. Furthermore, Fu et al demonstrated a significant positive association of MT1G hypermethylation with lymph node metastasis in 178 papillary thyroid cancer patients [ 89 ].…”

A case-control study of Metallothionein-1 expression in breast cancer and breast fibroadenoma

“…Metallothionein (MT) is a protein that has been widely studiedas a prognostic marker for breast cancer, since it promotes apoptosis, proliferation and differentiation of malignant tumor cells, making them more resistant to treatment 8–10 . Studies suggest that overexpression of metallothionein is associated with more aggressive breast tumors and more advanced-stage disease 11–14 .…”

An insight into the complex roles of metallothioneins in malignant diseases with emphasis on (sub)isoforms/isoforms and epigenetics phenomena

“…Sens et al showed that MT-3 over-expression was detected in breast cancer samples, and it was found to be associated with high recurrence rate (Sens, et al, 2001). In another study, however, MT-3 expression has been found to be lower in IDBC specimens compared with non-malignant breast tissues or mastopathies, in addition, the level of MT-3 mRNA was demonstrated to be even lower in breast cancers with lymph node metastasis than in carcinomas without metastasis (Gomulkiewicz, et al, 2016).…”

“…Noteworthy, they also revealed a negative correlation between invasiveness of ERα+ cells (MCF-7) and MT-1F and MT-1M expression, which thus may play an anti-oncogenic role. Distinct role was identified for MT-3, which is commonly silenced in normal breast tissue and breast-derived cell lines, but can be found in breast cancers tending to poor disease outcome (Gomulkiewicz, et al, 2016;Kmiecik, et al, 2015;Zeisig, Koklic, Wiesner, Fichtner, & Sentjurc, 2007). Interestingly, Somji et al revealed that treatment of non-tumorigenic MCF-10A cells with demethylation agent Decitabine or histone deacetylase inhibitor, Entinostat, restored the expression of MT-3 (Somji, et al, 2010), suggesting its epigenetic regulation.…”