Material and Method: Polyclonal rabbit β-catenin antibody was applied to 52 cases of infiltrative ductal carcinoma and 28 cases of ductal carcinoma in situ using the Avidin Biotin complex immune peroxidase method. The intensity and cellular localization of immunostaining were evaluated and compared.
Results: β-catenin immunoreactivity similar to that of normal epithelium was observed in 7 (8.75%) cases and weak or absent β-catenin expression was noted in 45 (56.25%) infiltrative ductal carcinoma cases. β-catenin expression was strong in 5 (6.25%) cases of ductal carcinoma in situ but weak or absent immunostaining was observed in 23 (28.75%) cases. Membranous β-catenin immunoreactivity was observed in 18 (22.5%) cases of infiltrative and 14 (%17.5) cases of ductal carcinoma in situ. Cytoplasmic immunostaining or complete absence of staining was noted in 34 (42.5%) cases of infiltrative and 14 (17.5%) cases of ductal carcinoma in situ.
Conclusion: Similar quantitative and qualitative changes in β-catenin expression were detected in a considerable proportion of in situ and infiltrative ductal carcinomas in the current study. These findings suggest that β-catenin plays a role in the carcinogenesis of infiltrative ductal carcinoma but similar expression patterns of β-catenin in infiltrative and in situ ductal carcinomas indicates that changes in β-catenin expression occur early in carcinogenesis.
The aim of the study was to compare β-catenin expression levels in ductal carcinoma in situ (DCIS) and infiltrating ductal carcinoma (IDC) of the breast and determine its role in the development of invasive tumor.
Figure 1: (+++) staining with β-catenin in ductal carcinoma in situ (β-catenin, x40).
Membranous staining was determined in 18 IDC cases (34.61%) (Figure 2) whereas cytoplasmic staining was observed in 29 IDC cases (55.78%). Membranous staining was detected in 14 DCIS cases (50%) and cytoplasmic staining in 11 DCIS cases (39.29%) (Table I). No significant difference was determined between DCIS and IDC in terms of staining pattern in the statistical analysis (p>0.05).
Figure 2: Membranous staining with β-catenin in infiltrating ductal carcinoma (β-catenin, x400).
Cancer progression is a spectrum starting from normal tissue and including hyperplasia, carcinoma in situ, invasive carcinoma and metastatic carcinoma. Cancer transition from the non-invasive to the invasive phase is the most important stage in progression[8]. Cell-cell and cell-matrix interactions play a role in every stage of metastasis. Adhesion molecules enable these interactions[9]. Essentially, changes should occur in cell-cell adhesions mediated by the cadherin family for a cancer cell to break free from the primary tumor. Interaction with catenins is essential for adhesive functions of E-cadherin which is a conventional cadherin type involved in Ca+2 mediated cellcell adhesion in epithelial cells and this interaction largely depends on β-catenin expression and function[5].
In addition to its adhesion function, β-catenin also interacts with tumor suppressor genes like APC and is involved in signal transduction pathways. Pathways containing β-catenin have been determined to play a major role in many neoplasia in recent studies.
Many studies regarding the expression of adhesion molecules in breast carcinomas have been conducted to date[10]. There are studies showing a decrease in the level of many adhesion molecules including integrin and E-cadherin in breast cancer[10].
β-catenin expression was demonstrated to be decreased or completely lost in cultured human breast cancer cell lines in studies[5,11]. This reduction may be associated with malignant transformation. Abnormal β-catenin expression was more frequently observed in invasive lobular carcinoma compared to infiltrating ductal carcinoma, and there is a complete loss of β–catenin immunoreactivity in some lobular carcinoma cases[5].
Jönsson et al. have revealed that β-catenin signals also play a role in human breast cancers by showing increased levels of cytosolic β-catenin in 13% of primary breast tumors[4].
Various IDC staining patterns and intensities have been found in different series[5,11,12]. On the other hand, Hashizume et al. have determined that E-cadherin, β-catenin and α-catenin were maintained in all cases of DCIS and 70% of IDC cases and consequently reported that these proteins do not play a primary role in cancer invasion[13]. They have assumed that the decrease in these proteins occur as a secondary event after main signals causing invasion such as protease production[13]. Our findings suggest that β-catenin has a role in the development of breast cancer.
β-catenin expression pattern is important. Normal β-catenin expression is membranous. β-catenin shows a strong membranous staining in breast epithelium cells[2]. Abnormally high amounts of β-catenin in the cytoplasm rather than within intracellular boundaries shows that the protein has acquired oncogenic potential.
Wong et al. found a high rate of cytoplasmic staining in breast tumor cells but failed to find nuclear staining in breast tumors in comparison with colon tumors[14]. Studies have shown that Wnt-1 and APC genes that are positive and negative regulators of β-catenin respectively, were maintained in invasive breast cancers and less frequent mutations of APC were found in breast cancers compared to colon cancers[4]. This also explains why there is no nuclear staining detected in breast cancers[15]. Nuclear staining was detected in none of the cases in this study and this is consistent with the literature.
The membranous staining pattern was lost in the majority of IDC and DCIS cases in our study and our findings were consistent with literature[5,16]. The increased levels of cytoplasmic β-catenin suggest that this may be one of the steps influential in the development of IDC.
Detection of similar changes in β-catenin expression in IDC and DCIS suggests that β-catenin does not have a primary contribution to invasion.
In conclusion, the lack of a statistically significant difference between DCIS and IDC in terms of β-catenin expression in our study shows that any change in β-catenin expression develops in early carcinogenesis. However, more comprehensive studies should be performed in order to demonstrate at what stage the change in β-catenin expression occurs.
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