Differential Expression Of E-Cadherin In Primary Breast Cancer And ...

Discussion

It is well-recognized that E-cadherin loss confirms invasive lobular carcinoma (17, 19, 20). The different pattern of E-cadherin expression in invasive ductal and lobular carcinomas suggests that this protein may play different roles in the development of each type of tumor. The absence of membranous E-cadherin expression in invasive lobular carcinomas may determine the morphological features such as the characteristic cellular arrangement of lobular carcinoma cells, as well as the distinct pattern of stromal invasion of invasive lobular carcinomas, typically as single cells or rows of cells (9). By comparing two sites, we determined that E-cadherin is expressed at normal levels at the distant metastatic site regardless of the level of expression at the site of primary invasive ductal carcinoma. Invasive lobular carcinomas have a different pattern of E-cadherin expression at primary and metastatic sites, which suggests a different role of E-cadherin in this form of cancer. Positive staining may not completely exclude the presence of lobular carcinoma because E-cadherin expression may be retained in a minority of cases with characteristic morphological features of lobular carcinoma. We consider that E-cadherin positivity favors ductal differentiation in ambiguous cases. In contrast, partial loss of E-cadherin expression in some poorly differentiated ductal carcinomas is not of diagnostic significance.

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Molecular subtypes and E-Cadherin expression in no special type (NST) primary breast cancer and paired lymph node metastases (LNM).

The absence of E-cadherin expression is frequently described in correlation with tumor size and stage, lymph node status, tumoral recurrence, and grade of differentiation. Moreover, Goldstein considered that its lack of expression explains the distinctive growth patterns in metastases (21). Kowalski et al. consider that a reduction in E-cadherin expression is frequent in invasive ductal carcinomas that will progress and develop distant metastases (9).

By studying E-cadherin expression in primary breast tumors and their corresponding metastases to liver, lung and brain, Chao et al. showed an increased expression (62%) in the metastases compared to the primaries (22). In addition, it has been observed that metastatic foci commonly appear to be more differentiated than the corresponding primary tumor, suggesting that cancer cells may further undergo a mesenchymal to epithelial reverting transition in the secondary organ environment.

However, our results showed E-cadherin expression to be less frequent in LNM (72.73%) than in primary sites (95.45%). E-Cadherin loss in the lymph node environment supports the possibility of epithelial-mesenchymal transition in breast carcinomas metastasis. Although it was shown that abnormality of E-cadherin expression and methylation of its gene is associated with an aggressive clinical course, Hollestelle et al. concluded that loss of E-cadherin is not a necessity for epithelial-mesenchymal transition in human breast cancer (23).

The loss of E-cadherin expression has an unfavorable prognostic significance. Its absence is frequently associated with metastatic lymph node status, tumor recurrence, low grade of differentiation, and advanced stage of tumor (24). It has been demonstrated that low colony-forming activity of human breast cancer cells of the luminal subtype is accompanied by increased adhesive properties of these cells due to a high level of E-cadherin expression (11). High tumorigenicity of cells of the basal subtype is related to weakening of adhesive contacts that is caused by abnormalities of E-cadherin expression.

Recently several studies have described the possibility of a phenotype switch during the metastatic process. It is hypothesized that the molecular profile of breast canceris not stable throughout tumor progression. Moreover, Falck et al. found that when a shift in molecular subtype between primary tumor and metastatic lymph node occurs, the prognosis (for 10 years) follows the subtype from metastasis (25).

Nowadays, E-cadherin is considered to be an independent marker of triple-negative breast cancer, a molecular subtype characterized with poor prognosis and short survival (12). In our investigation the molecular subtypes of the primary sites did not correspond 100% with those of their LNM. In particular, we observed a shift from luminal to triple-negative. This transition is supported by a decrease in the E-cadherin-positive rate from 95.45% in primary tumors to 72.73% in LNM (Table II) and higher incidence of the triple-negative subtype in LNM (15.91% versus 10.23% in primary sites). However, statistically confirmed correlation between E-cadherin and the molecular subtype of primary carcinoma and LNM was not found. Our results are contradictory to certain recent data (13), which revealed statistically significant differences in E-cadherin expression by molecular subtype. Bertolo et al. found a positive correlation of E-cadherin and HER2 receptor, but in our study, E-cadherin in primary sites correlated positively only with E-cadherin in LNM (26). This contradiction may be due to the selected study material. Authors selected cases without distant metastasis at the time of primary diagnosis. In addition, we processed a higher number of cases (88 versus 60).

E-Cadherin in LNM correlated only with ER at the same site. It should be noted that despite the obtained results being statistically significant (p≤0.05), correlations were graded as weak. E-Cadherin correlation with the molecular profile in breast carcinomas needs further investigation by other groups.