Molecular basis of incomplete O-glycan synthesis in MCF-7 breast cancer cells: putative role of MUC6 in Tn antigen expression.

International audienceAn incomplete elongation of O-glycan saccharide chains in mucins have been found in epithelial cancers, leading to the expression of shorter carbohydrate structures, such as the Tn antigen (GalNAc-O-Ser/Thr). This antigen is one of the most specific human cancer-associated structures and is capable of inducing effective immune responses against cancer cells. We aimed to investigate the causes of the expression of Tn antigen in the Tn-rich MCF-7 breast cancer cell line focusing on the first step of the O-glycosylation process. Interestingly, amino acid sequences derived from "non-mammary" apomucins (MUC5B and MUC6) were very good acceptor substrates for ppGalNAc-Ts, which are the enzymes catalyzing the Tn antigen synthesis. MUC6 peptide glycosylation with MCF-7 microsome extracts as source of ppGalNAc-T activity yielded 95% conversion of the peptide into MUC6-Tn. In addition, the MUC6-Tn glycopeptide was a poor acceptor substrate for core 1 beta3Gal-T, the next enzyme involved in the saccharide chain biosynthesis, yielding only 5% conversion of MUC6-Tn into MUC6-TF. These results indicate that non-mammary apomucin expression could be responsible, at least in part, for Tn antigen expression in MCF-7 breast cancer cells due to a combined action on glycosyltransferases: an increase of ppGalNAc-T activity and a decrease of core 1 beta3Gal-T activity. Our hypothesis is supported by experiments in vivo showing that (a) native MUC6 glycoproteins express the Tn antigen in MCF-7 cells and (b) Tn antigen expression is increased after transfection with a construct encoding for a MUC6 recombinant protein into the low Tn-expressing breast cancer cell T47D. These results open new horizons in breast cancer glycoimmunology, stressing the potential role of non-mammary apomucins

Natural and Induced Humoral Responses to MUC1

cancer

High level of MUC1 in serum of ovarian and breast cancer patients inhibits huHMFG-1 dependent cell-mediated cytotoxicity (ADCC)

The huHMFG-1 (AS1402) antibody is a humanised IgG1 directed against MUC1 and is currently in clinical trials for the treatment of breast carcinoma. Adenocarcinomas over-express and shed MUC1, and high MUC1 serum levels are associated with progressive disease. Here, we have investigated the effects of MUC1 present in sera from breast and ovarian cancer patients and that of NK cells on in vitro huHMFG-1-mediated ADCC, performed with and without the addition of various cytokines. Screening for patients with high levels of NK cells bearing the FcγRIIIa-158V polymorphism, adjusting the dosage to circulating levels of MUC1 and co-administration of NK cell activating cytokines may increase the efficacy of huHMFG-1 treatment

Serum CA-125 in relation to adnexal dysplasia and cancer in women at hereditary high risk of ovarian cancer

Purpose: Serum CA-125 level is commonly used as indicator for ovarian cancer recurrence. However, its value for the prediction of neoplastic lesions is unknown. The aim of this study was to investigate whether CA-125 concentrations are indicative of adnexal dysplasia and cancer in women at hereditary high risk of ovarian/tubal cancer. Patients and Methods: CA-125 was obtained from 424 women at hereditary high risk of ovarian/tubal cancer attending the VU University Medical Center (Amsterdam, the Netherlands) between 1993 and 2005. Serum samples obtained at the second-to-last (n = 64) and last (n = 98) visit before surgery were tested in women who underwent adnexal surgery for diagnostic (n = 9) or prophylactic (n = 89) reasons. Serum samples obtained from 370 age-matched healthy women were used as controls. Results: Both the absolute value (P < .0001) and the serial change (P < .0001) of CA-125 were predictive for ovarian cancer (n = 8). For adnexal dysplasia (n = 23), the absolute value of CA-125 (P = .003) was predictive, but the serial change in CA-125 was not (P = .32). The odds ratio for adnexal dysplasia versus nondysplasia in the highest tertile (CA-125 levels ≥ 14 U/mL) compared with the lowest tertile (CA-125 < 10 U/mL) was 6 (95% CI, 1.32 to 36.66). Conclusion: In patients at hereditary high risk for adnexal cancer, both the absolute value of serum CA-125 and the change in serial CA-125 are predictors for ovarian cancer. Remarkably, the absolute value of CA-125 is also predictive for adnexal dysplasia. CA-125 values should, therefore, be taken into account in the decision toward prophylactic bilateral salpingo-oophorectomy