A1 Vertaisarvioitu alkuperäisartikkeli tieteellisessä lehdessä
Mammary-derived growth inhibitor alters traffic of EGFR and induces a novel form of cetuximab resistance
Tekijät: Nevo J, Mattila E, Pellinen T, Yamamoto DL, Sara H, Iljin K, Kallioniemi O, Bono P, Heikkilä P, Joensuu H, Wärri A, Ivaska J
Julkaisuvuosi: 2009
Journal: Clinical Cancer Research
Tietokannassa oleva lehden nimi: Clinical cancer research : an official journal of the American Association for Cancer Research
Lehden akronyymi: Clin Cancer Res
Vuosikerta: 15
Numero: 21
Aloitussivu: 6570
Lopetussivu: 81
Sivujen määrä: 12
ISSN: 1078-0432
DOI: https://doi.org/10.1158/1078-0432.CCR-09-0773
Tiivistelmä
MDGI-driven inherent desensitization of cancer cells is a novel molecular mechanism for resistance to the anti-EGFR antibody therapy, and MDGI may be a biomarker for responsiveness to anti-EGFR antibody therapy.\nOnly few predictive factors for the clinical activity of anti-epidermal growth factor receptor (EGFR) therapy are available. Mammary-derived growth inhibitor (MDGI) is a small cytosolic protein suggested to play a role in the differentiation of epithelial cells. Here, we have investigated the effect of MDGI expression on the EGFR signaling and cetuximab responsiveness of cancer cells.\nMDGI mRNA expression was investigated in clinical breast and lung cancer samples and in nontransformed and malignant cell lines. The effect of ectopic expression of MDGI on EGFR, ErbB2, and integrin function and traffic was investigated in breast and lung cancer cell lines using multiple methods. The effect of anti-EGFR agents on these cells were tested by cell proliferation measurements and by assessing tumor growth of breast cancer cells in cetuximab treated and control athymic nude mice.\nHere, we show that although MDGI is absent in cultured cell lines because of epigenetic silencing, MDGI mRNA is expressed in 40% of clinical breast carcinomas and 85% of lung cancers. Ectopic expression of MDGI rendered breast and lung cancer cells resistant to the anti-EGFR antibody cetuximab in vitro and in an orthotopic breast cancer xenograft model in vivo. When expressed in cancer cells, MDGI induces intracellular accumulation of EGFR, but not ErbB2, and the internalized receptor is phosphorylated and not degraded.\nCONCLUSIONS\nPURPOSE\nEXPERIMENTAL DESIGN\nRESULTS
MDGI-driven inherent desensitization of cancer cells is a novel molecular mechanism for resistance to the anti-EGFR antibody therapy, and MDGI may be a biomarker for responsiveness to anti-EGFR antibody therapy.\nOnly few predictive factors for the clinical activity of anti-epidermal growth factor receptor (EGFR) therapy are available. Mammary-derived growth inhibitor (MDGI) is a small cytosolic protein suggested to play a role in the differentiation of epithelial cells. Here, we have investigated the effect of MDGI expression on the EGFR signaling and cetuximab responsiveness of cancer cells.\nMDGI mRNA expression was investigated in clinical breast and lung cancer samples and in nontransformed and malignant cell lines. The effect of ectopic expression of MDGI on EGFR, ErbB2, and integrin function and traffic was investigated in breast and lung cancer cell lines using multiple methods. The effect of anti-EGFR agents on these cells were tested by cell proliferation measurements and by assessing tumor growth of breast cancer cells in cetuximab treated and control athymic nude mice.\nHere, we show that although MDGI is absent in cultured cell lines because of epigenetic silencing, MDGI mRNA is expressed in 40% of clinical breast carcinomas and 85% of lung cancers. Ectopic expression of MDGI rendered breast and lung cancer cells resistant to the anti-EGFR antibody cetuximab in vitro and in an orthotopic breast cancer xenograft model in vivo. When expressed in cancer cells, MDGI induces intracellular accumulation of EGFR, but not ErbB2, and the internalized receptor is phosphorylated and not degraded.\nCONCLUSIONS\nPURPOSE\nEXPERIMENTAL DESIGN\nRESULTS
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