Over‐expression of metallothionein predicts chemoresistance in breast cancer

Abstract

Metallothionein (MT) plays a role in fundamental cellular processes such as proliferation, apoptosis and differentiation. We examined MT expression in women with invasive breast ductal carcinoma who underwent mastectomy/lumpectomy without neo-adjuvant treatment. We showed that MT was over-expressed in 87.9% of breast cancer tissues examined, with the mean percentage of positive cells at 30%. There were two patterns of MT expression: predominantly cytoplasmic in 75.9% and nuclear in 24.1% of MT-positive cases. Higher MT scores were associated with poorer histological grade (p = 0.009) but were independent of age, tumour size and oestrogen receptor status. For patients who were treated with adjuvant chemotherapy (cyclophosphamide/methotrexate/5 fluorouracil- or doxorubicin-based regimes), those with high MT expression had a significantly lower recurrence-free survival (p = 0.048), suggesting a role of MT in predicting disease recurrence. Down-regulation of MT in MCF-7 cells by silencing the MT-2A gene (the most abundantly expressed of the 10 known functional MT isoforms) increased chemosensitivity of the cells to doxorubicin. To examine the mechanisms underlying these clinical data, we used siRNAs to decrease MT-2A mRNA expression and protein expression. In MT down-regulated cells challenged with the IC(50) concentration of doxorubicin, we observed a significant reduction in cell viability. Cell cycle analysis also revealed a corresponding increase in apoptosis in the MT down-regulated cells following doxorubicin exposure, showing that down-regulation of MT increased susceptibility to doxorubicin cytotoxicity. The data suggest that MT could be a potential marker of chemoresistance and a molecular therapeutic target.

Correlation between metallothionein (MT) expression and selected prognostic factors in ductal breast cancers.

“…Jin et al found that in breast cancer cases of the highest malignancy G3, expression of MT was significantly higher than in better differentiated cases, G1 and G2 [41,44]. Similar observations were made recently by Yap et al [36]. In turn, Gallicchio et al in the studied group of 110 cases of ductal breast cancer demonstrated a strong positive correlation between intensity of MT expression and grade of malignancy [45].…”

“…Several authors showed an evident relationship between intensity of MT expression and clinical advancement of the tumours, frequency of metastasis development, as well as shortening of survival rate and disease free survival [17,28,[31][32][33][34]. In some tumours also a significant correlation between high levels of MT and unfavourable results of treatment was observed [30,35,36].…”

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

“…Although metatypic BCC is regarded as an aggressive subtype of BCC, it manifested the lowest MT-I/II expression of the analyzed subtypes. We used IHC techniques to determine MT-I/II expression, but recent studies have shown that only particular MT-I/II isoforms may contribute to cancer cell aggressiveness in some tumor types [31][32][33][34][35]. In our study, we noted the highest Ki-67 antigen expression in this subtype.…”

Overexpression of the drug resistance‐associated protein metallothionein does not correlate with response of sarcomas to isolated limb perfusion treatment

“…Several studies have reported MT expression in various human malignancies including STSs and BSs [6][7][8][9], and there is evidence that MT plays a role in cancer development [10], prognosis [6], and treatment resistance [11]. With respect to cancer therapy, MT can protect against radiation therapy [12] and anticancer drugs [10,13], most likely due to their anti-oxidant properties. Remarkably, MT can counteract the effect of melphalan [14,15], the active cytotoxic component of HILP-TM treatment.…”