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Co-targeting the insulin-like growth factor I receptor enhances growth-inhibitory and pro-apoptotic effects of anti-estrogens in human breast cancer cell lines

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Abstract

The insulin-like growth factor I receptor (IGF1R) interacts with estrogen receptor-α (ERα) and HER2. We examined the effect of combinations of IGF1R antagonists (α-IR3, AG1024) and anti-estrogens (4-hydroxy tamoxifen, fulvestrant) in two human ER+ breast cancer cell lines: BT474 (HER2 overexpressing, IGF1R low) and MCF7 (HER2 non-overexpressing, IGF1R high). In BT474 cells, growth was inhibited by anti-estrogens, but not by IGF1R antagonists; however, adding IGF1R inhibitors to anti-estrogens enhanced growth inhibition. In MCF7 cells, growth was inhibited by IGF1R and ER antagonists and more so by their combination. In both cell lines, no single agents could induce apoptosis, but combining IGF1R inhibitors with anti-estrogens induced dramatic levels of apoptosis. IGF1R antagonists enhanced the ability of the anti-estrogens to inhibit ER transcriptional activity in BT474 cells, but not in MCF7 cells. The drug combination synergistically inhibited ER and IGF1R activity. Such combinations may be useful therapy for breast cancer.

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Acknowledgments

Supported by grants from the Breast Cancer Research Foundation to MPD. We thank Dr. Marc Lippman for MCF7 cells and advice on their use, Dr. Rocco Carbone of the Yale Cancer Center Flow Cytometry shared resource (supported by US Public Health Service grant CA-16359 from the National Cancer Institute) for assistance with flow cytometry, and Cynthia Zerillo for helpful suggestions.

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Authors and Affiliations

  1. Departments of Internal Medicine (Section of Medical Oncology) and Pharmacology, and the Yale Cancer Center, Yale University School of Medicine, 333 Cedar Street, Room WWW217, New Haven, CT, 06510, USA

    Ashok K. Chakraborty, Allison Welsh & Michael P. DiGiovanna

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  1. Ashok K. Chakraborty
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  2. Allison Welsh
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  3. Michael P. DiGiovanna
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Correspondence to Michael P. DiGiovanna.

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Chakraborty, A.K., Welsh, A. & DiGiovanna, M.P. Co-targeting the insulin-like growth factor I receptor enhances growth-inhibitory and pro-apoptotic effects of anti-estrogens in human breast cancer cell lines. Breast Cancer Res Treat 120, 327–335 (2010). https://doi.org/10.1007/s10549-009-0382-5

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