The expression of E-cadherin in breast cancer metastases is largely unknown and, to our knowledge, there are no studies that specifically investigate the expression of E-cadherin in primary breast carcinomas in relationship to their distant metastases. We found that aberrant E-cadherin expression is a common event in primary invasive ductal carcinomas that progress to develop distant metastases, as aberrant expression was found in 45% of these cases.
There is increasing evidence that cancer cells may re-express E-cadherin protein once they reach distant sites. We found that all the metastatic deposits from invasive ductal carcinomas expressed E-cadherin, and the degree of expression was either equal to or stronger than that of the primary tumor. By studying E-cadherin expression in nodal breast cancer metastases, Bukholm and colleagues found that 19 of 20 lymph node metastases strongly expressed E-cadherin protein [21
]. The mechanism and biologic role of E-cadherin re-expression at the metastatic site has not been elucidated, although it appears that translational regulation and post-translational events are probable mechanisms of E-cadherin re-expression [31
In order to metastasize, cancer cells must break away from the primary tumor, move into the surrounding stroma, intravasate into the circulation, extravasate, and successfully re-establish growth at other sites. It is possible that loss of E-cadherin is a transient phenomenon that allows malignant cells to invade vascular channels and tissues. We have previously demonstrated that intralymphatic breast cancer emboli strongly express E-cadherin protein, and we postulate that re-expression of E-cadherin occurs in the circulating tumor cells, enabling the cancer cells to form tumor emboli and to survive [28
]. E-cadherin re-expression may also enable malignant cells to form a metastatic deposit by facilitating intercellular adhesion. The normal expression or re-expression of E-cadherin in cancer metastases appears to be similar in breast cancer and prostate cancer. Rubin and colleagues studied a large group of prostate cancers that included 77 distant metastases and detected normal E-cadherin expression in 90% of these cases [29
In breast cancer, a relationship between E-cadherin expression and ER expression has been noted previously. ER-positive tumors have been demonstrated to express normal amounts of E-cadherin protein, and loss of ER and E-cadherin genes has been linked to disease progression in invasive carcinomas of the breast. Nass and colleagues found an association between coincident methylation of E-cadherin and the ER gene during breast cancer progression, probably not attributable to coincidence of methylation for the two genes [32
]. In our study, however, we did not find an association between E-cadherin expression and the ER, PR or HER-2/neu status.
The role of E-cadherin in the pathogenesis and progression of invasive lobular carcinoma is intriguing. We found that all of the primary invasive lobular carcinomas and nearly all of the metastatic foci had accumulation of E-cadherin protein in the cytoplasm of the neoplastic cells, with no membranous staining. Several studies have demonstrated that E-cadherin is commonly downregulated in invasive lobular carcinomas [33
]. Berx and colleagues found somatic mutations of the E-cadherin gene in 56% (27/48 cases) of invasive lobular carcinomas, and 90% of these tumors had allelic losses at the E-cadherin locus. No mutations were identified in 50 nonlobular breast cancers [34
]. Sarrio and colleagues recently reported that promoter hypermethylation is another common mechanism of E-cadherin inactivation in invasive lobular carcinomas, occurring in 41% (19/46) of cases [36
]. De Leeuw and colleagues reported that 84% (32/38) of invasive lobular carcinomas had completely absent membranous staining by immunohistochemistry, and 56% of these cases had staining in the cytoplasm of the cancer cells [33
The clearly 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 specific type of tumor. The absence of membranous E-cadherin expression in invasive lobular carcinomas may determine the morphologic features such as the characteristic cellular discohesion of the lobular carcinoma cells, as well as the distinct pattern of stromal invasion of invasive lobular carcinomas, typically as single cells or rows of cells.
In summary, the present study provides evidence that approximately one-half of the invasive ductal carcinomas that develop distant metastases have aberrant E-cadherin protein expression. E-cadherin is expressed or re-expressed at the distant metastatic foci of invasive ductal carcinomas, supporting the hypothesis that re-expression of E-cadherin may play a role in the establishment of the metastatic cells at distant sites. Invasive lobular carcinomas have a different pattern of E-cadherin expression both at the primary carcinoma and the metastatic sites, which suggests a different role for E-cadherin in this form of breast cancer.