CD46 Expression is an Unfavorable Prognostic Factor in Breast Cancer Cases
ABSTRACT The membrane cofactor protein, CD46 represents a complement inhibitor, which protects autologous cells from complement-mediated cytotoxicity. On tumor cells, CD46 may exhibit the potential to protect them from immune responses of the host. The present study aimed at evaluation of prognostic significance of CD46 expression in breast cancers. The analyses were performed on 70 samples of breast cancer. Immunohistochemical reactions were performed on paraffin sections of studied tumors using monoclonal antibodies directed against CD46. Results of the immunohistochemical reactions and of clinical observations were subjected to statistical analysis. Multivariate analysis showed that expression of CD46 and involvement of lymph nodes represent independent risk factors for disease-free survival and overall survival. Kaplan-Meier analysis showed that patients with tumors negative for CD46 have an increased progression-free time and overall survival time as compared with patients with the CD46-positive tumors. The study demonstrates that breast cancers manifest CD46 expression and that it is linked to a less favorable prognosis.
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ABSTRACT: CD46 is one of the complement-regulatory proteins expressed on the surface of normal and tumor cells for protection against complement-dependent cytotoxicity. Cancer cells need to access the blood circulation for continued growth and metastasis, thus exposing themselves to destruction by complement system components. Previous studies have established that the signal transducers and activators of transcription 3 (STAT3) transcription factor is persistently activated in a wide variety of human cancer cells and primary tumor tissues compared with their normal counterparts. Using microarray gene expression profiling, we identified the CD46 gene as a target for activated STAT3 signaling in human breast and prostate cancer cells. The CD46 promoter contains two binding sites for activated STAT3 and mutations introduced into the major site abolished STAT3 binding. Chromatin immunoprecipitation confirms binding of STAT3 to the CD46 promoter. CD46 promoter activity is induced by activation of STAT3 and blocked by a dominant-negative form of STAT3 in luciferase reporter assays. CD46 mRNA expression is induced by interleukin-6 and by transient transfection of normal human epithelial cells with a persistently active mutant construct of STAT3, STAT3C. Furthermore, we show that inhibition of STAT3-mediated CD46 cell surface expression sensitizes DU145 prostate cancer cells to cytotoxicity in an in vitro complement lysis assay using rabbit anti-DU145 antiserum and rabbit complement. These results show that activated STAT3 signaling induces the CD46 promoter and protects human cancer cells from complement-dependent cytotoxicity, suggesting a potential mechanism whereby oncogenic signaling contributes to tumor cell evasion of antibody-mediated immunity.Molecular Cancer Research 09/2007; 5(8):823-32. DOI:10.1158/1541-7786.MCR-06-0352 · 4.50 Impact Factor
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ABSTRACT: Monoclonal antibodies (mAbs) are being increasingly used in cancer therapy owing to their ability to recognize specifically cancer cells and to activate complement- and cell-mediated cytotoxicity and/or to induce growth arrest or apoptosis. The therapeutic potential of anticancer antibodies is significantly limited due to the ability of cancer cells to block killing by complement. Of the multiple resistance strategies exploited by cancer cells, the expression of membrane complement regulatory proteins (mCRPs), such as CD46 (membrane cofactor protein (MCP)), CD55 (decay-accelerating factor (DAF)), CD35 (complement receptor type-1 (CR1)) and CD59, has received most attention. CD46, CD55 and CD35 block the complement cascade at the C3 activation stage and CD59 prevents assembly of the membrane attack complex of complement (MAC). These proteins protect normal tissues from accidental injury by activated complement, but also confer resistance on cancer cells, thereby limiting the effect of complement-fixing monoclonal antibodies. Expression of mCRPs on malignant cells is highly variable, yet there is clear indication that certain tumors express higher mCRP levels than the normal tissue from which they have evolved. mCRP level of expression and cellular location may also vary during malignant transformation and between differentiated and undifferentiated tumors. Neutralizing anti-mCRP mAbs have been used in vitro to elucidate the significance of mCRP expression to the tumor complement resistance phenotype. In general, CD59 appears to be the most effective mCRP protecting tumor cells from complement-mediated lysis. Nevertheless, it acts additively, and in certain tumors even synergistically, with CD55 and CD46. It is envisaged that treatment of cancer patients with mCRP blocking antibodies targeted specifically to cancer cells in combination with anticancer complement-fixing antibodies will improve the therapeutic efficacy.Molecular Immunology 10/2003; 40(2-4):109-23. DOI:10.1016/S0161-5890(03)00112-3 · 3.00 Impact Factor