Mammary-Derived Growth Inhibitor Alters Traffic of EGFR and Induces a Novel Form of Cetuximab Resistance

Jonna Nevo, Elina Mattila, Teijo Pellinen, Daniel L. Yamamoto, Henri Sara, Kristiina Iljin, Olli Kallioniemi, Petri Bono, Päivi Heikkilä, Heikki Joensuu, Anni Wärri, Johanna Ivaska

Research output: Contribution to journalArticleScientificpeer-review

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Abstract

Purpose: Only 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.

Experimental Design: MDGI 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.

Results: Here, 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.

Conclusions: 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.(Clin Cancer Res 2009;15(21):6570–81)
Original languageEnglish
Pages (from-to)6570-6581
Number of pages12
JournalClinical Cancer Research
Volume15
Issue number21
DOIs
Publication statusPublished - 2009
MoE publication typeA1 Journal article-refereed

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Growth Inhibitors
Breast
Breast Neoplasms
Lung Neoplasms
Anti-Idiotypic Antibodies
Nude Mice
Cell Line
Neoplasms
Cetuximab
Messenger RNA
Growth Factor Receptors
Heterografts
Epigenomics
Integrins
Cultured Cells
Research Design
Therapeutics
Biomarkers
Epithelial Cells
Cell Proliferation

Cite this

Nevo, Jonna ; Mattila, Elina ; Pellinen, Teijo ; Yamamoto, Daniel L. ; Sara, Henri ; Iljin, Kristiina ; Kallioniemi, Olli ; Bono, Petri ; Heikkilä, Päivi ; Joensuu, Heikki ; Wärri, Anni ; Ivaska, Johanna. / Mammary-Derived Growth Inhibitor Alters Traffic of EGFR and Induces a Novel Form of Cetuximab Resistance. In: Clinical Cancer Research. 2009 ; Vol. 15, No. 21. pp. 6570-6581.
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title = "Mammary-Derived Growth Inhibitor Alters Traffic of EGFR and Induces a Novel Form of Cetuximab Resistance",
abstract = "Purpose: Only 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.Experimental Design: MDGI 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.Results: Here, 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.Conclusions: 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.(Clin Cancer Res 2009;15(21):6570–81)",
author = "Jonna Nevo and Elina Mattila and Teijo Pellinen and Yamamoto, {Daniel L.} and Henri Sara and Kristiina Iljin and Olli Kallioniemi and Petri Bono and P{\"a}ivi Heikkil{\"a} and Heikki Joensuu and Anni W{\"a}rri and Johanna Ivaska",
year = "2009",
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language = "English",
volume = "15",
pages = "6570--6581",
journal = "Clinical Cancer Research",
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Nevo, J, Mattila, E, Pellinen, T, Yamamoto, DL, Sara, H, Iljin, K, Kallioniemi, O, Bono, P, Heikkilä, P, Joensuu, H, Wärri, A & Ivaska, J 2009, 'Mammary-Derived Growth Inhibitor Alters Traffic of EGFR and Induces a Novel Form of Cetuximab Resistance', Clinical Cancer Research, vol. 15, no. 21, pp. 6570-6581. https://doi.org/10.1158/1078-0432.CCR-09-0773

Mammary-Derived Growth Inhibitor Alters Traffic of EGFR and Induces a Novel Form of Cetuximab Resistance. / Nevo, Jonna; Mattila, Elina; Pellinen, Teijo; Yamamoto, Daniel L.; Sara, Henri; Iljin, Kristiina; Kallioniemi, Olli; Bono, Petri; Heikkilä, Päivi; Joensuu, Heikki; Wärri, Anni; Ivaska, Johanna.

In: Clinical Cancer Research, Vol. 15, No. 21, 2009, p. 6570-6581.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - Mammary-Derived Growth Inhibitor Alters Traffic of EGFR and Induces a Novel Form of Cetuximab Resistance

AU - Nevo, Jonna

AU - Mattila, Elina

AU - Pellinen, Teijo

AU - Yamamoto, Daniel L.

AU - Sara, Henri

AU - Iljin, Kristiina

AU - Kallioniemi, Olli

AU - Bono, Petri

AU - Heikkilä, Päivi

AU - Joensuu, Heikki

AU - Wärri, Anni

AU - Ivaska, Johanna

PY - 2009

Y1 - 2009

N2 - Purpose: Only 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.Experimental Design: MDGI 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.Results: Here, 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.Conclusions: 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.(Clin Cancer Res 2009;15(21):6570–81)

AB - Purpose: Only 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.Experimental Design: MDGI 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.Results: Here, 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.Conclusions: 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.(Clin Cancer Res 2009;15(21):6570–81)

U2 - 10.1158/1078-0432.CCR-09-0773

DO - 10.1158/1078-0432.CCR-09-0773

M3 - Article

VL - 15

SP - 6570

EP - 6581

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 21

ER -