Levels of expression of breast epithelial mucin detected by monoclonal antibody BrE‐3 in breast‐cancer prognosis

Abstract

Taking into consideration the relationship of breast neoplasia with recent knowledge obtained on the molecular structure and biosynthesis of the breast epithelial mucin, an epitope on this molecule detected by monoclonal antibody (MAb) BrE-3 was chosen as a marker to study the correlation of expression of the mucin and prognosis in infiltrating ductal carcinomas of the breast. Strong statistical validation was obtained in the use of BrE-3 in immunohistochemical procedures where scores for the expression of the mucin on paraffin-embedded sections of the primary breast tumors were studied. Four different immunohistochemical variables measuring levels of expression (intensity or prevalence) in cytoplasm or membrane were obtained for each of 227 patients' breast tumors and subjected to Kaplan-Meier univariate and Cox proportional-hazards multi-variate analysis. Additionally, traditional prognostic variables for breast-cancer prognosis (grade of differentiation, age, tumor size, axillary-lymph-node involvement and estrogen receptors) were subjected to identical analyses. In uni-variate analysis, low cytoplasmic intensity, high membrane prevalence, and high membrane intensity of mucin expression were each found to be significantly associated with good prognosis in relation to both survival or relapse time. In multi-variate analysis, all 4 immunohistochemical parameters were significantly associated with both survival and relapse time in these patients. Among the traditional variables, 3 (axillary-node involvement, grade of differentiation and tumor size) were also found to be statistically significant at the uni-variate and multi-variate level. A multi-variate analysis of the combined immunohistochemical and traditional variables identified the 4 immunohistochemical parameters, tumor size and axillary-node involvement as having the highest level of association with either survival or relapse time. These variables were then combined and served to define a prognostic model [ILCPS(Comb)], which was found to have the capacity to separate the patient population studied into 4 prognostic groups in terms of survival and 3 groups in terms of relapse. As expected, the ILCPS(Comb) was shown to have a higher level of prognostic association with both survival and relapse than the individual variables themselves, the traditional variables together or the immunohistochemical variables together. Our approach develops a theoretical framework and a statistical model, employing levels of expression of the breast epithelial mucin and 3 traditional variables, which identifies, in terms of prognosis, distinct sub-populations of patients with infiltrating breast carcinoma with defined risk functions.

MUC1 and the MUCs: A Family of Human Mucins with Impact in Cancer Biology

“…252−254 In some studies using mabs BrE-3 and BC2, a significant association of cytoplasmic MUC1 expression and a poorer survival was observed applying the mabs BrE-3 and BC2. 252,255 The same prognostic relevance was observed for BC2 staining irrespective of the subcellular MUC1 localization. 252 Lymphnodal metastasis was also more extensive in tumors with a strong expression of BC2 252 and EMA.…”

Characterization of MUC1 glycoprotein on prostate cancer for selection of targeting molecules

“…Seven mouse MAbs were chosen to evaluate MUC1 epitopes: B27.29, EMA, BC2, NCL-MUC1 Core, HMFG-1, BrE-3 and SM3 (Table I). With the exception of BrE-3, all of these MAbs were characterized extensively in the 1998 Workshop on MUC1 MAbs (42); in vitro and in vivo binding of BrE-3 has been described elsewhere (19,22,23,27,(43)(44)(45). MAb characterization included comparison for core peptide epitopes (46), VNTR affinity (47), effect of glycosylation on binding to VNTR (48), ability to bind to highly glycosylated (49) and hypoglycosylated cell lines (50) and binding to normal MUC1-expressing tissues (breast, small intestine, colon) (51).…”

“…Higher expression of aberrant forms of the MUC1 glycoprotein have been observed in a number of cancers (15)(16)(17)(18)(19)(20). Expression of MUC1 epitopes with reduced branching of O-glycans has been observed in breast cancer tissue (18,21) and was reflected by increased staining with MAbs recognizing hypoglycosylated MUC1 (17,20,(22)(23)(24)(25)(26)(27). However, not all cancers express high levels of hypoglycosylated MUC1 epitopes and cancer progression is not always associated with this MUC1 form (11,28,29).…”

Pathogenesis of invasive micropapillary carcinoma: role of MUC1 glycoprotein

“…[26][27][28][29][30] Intercellular/circumferential labeling was associated with a high incidence of lymph node metastases as well. 28 Interestingly, none of these labeling patterns (intracytoplasmic or intercellular) is seen in invasive micropapillary carcinoma despite the high propensity of the tumor for lymph node metastases and its poor prognosis.…”