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Estrogen and insulin-like growth factor-I (IGF-I) independently down-regulate critical repressors of breast cancer growth

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Abstract

Although estrogen receptor alpha (ERα) and insulin-like growth factor (IGF) signaling are important for normal mammary development and breast cancer, cross-talk between these pathways, particularly at the level of transcription, remains poorly understood. We performed microarray analysis on MCF-7 breast cancer cells treated with estradiol (E2) or IGF-I for 3 or 24 h. IGF-I regulated mRNA of five to tenfold more genes than E2, and many genes were co-regulated by both ligands. Importantly, expression of these co-regulated genes correlated with poor prognosis of human breast cancer. Closer examination revealed enrichment of repressed transcripts. Interestingly, a number of potential tumor suppressors, for example, B-cell linker (BLNK), were down-regulated by IGF-I and E2. Analysis of three down-regulated genes showed that E2-mediated repression occurred independently of IGF-IR, and IGF-I-mediated repression occurred independently of ERα. However, repression by IGF-I or E2 required common kinases, such as PI3K and MEK, suggesting downstream convergence of the two pathways. In conclusion, E2 and IGF-I co-regulate a set of genes that affect breast cancer outcome. There is enrichment of repressed transcripts, and, for some genes, the down-regulation is independent at the receptor level. This may be important clinically, as tumors with active ERα and IGF-IR signaling may require co-targeting of both pathways.

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Acknowledgments

This work was supported by grants from the Department of Defense Breast Cancer Research Program W81XWH-06-1-0714 (AJC) and BC043880 (SM), and by grants from the National Institutes of Health P01CA30195 (AVL), P30CA58183 (AVL), and R01CA097213 (SO).

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Authors and Affiliations

  1. Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, 77030, USA

    Angelo J. Casa, Adam S. Potter, Simeen Malik, ZaWaunyka Lazard, Isere Kuiatse, Hee-Tae Kim, Anna Tsimelzon, Susan G. Hilsenbeck, Powell H. Brown, Steffi Oesterreich & Adrian V. Lee

  2. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA

    Angelo J. Casa, Adam S. Potter, Simeen Malik, Powell H. Brown, Steffi Oesterreich & Adrian V. Lee

  3. Department of Medicine, Baylor College of Medicine, Houston, TX, 77030, USA

    Anna Tsimelzon, Chad J. Creighton, Susan G. Hilsenbeck, Powell H. Brown, Steffi Oesterreich & Adrian V. Lee

  4. Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, 77030, USA

    Chad J. Creighton

  5. Department of Pharmacology and Chemical Biology, University of Pittsburgh Cancer Institute, Magee Women’s Research Institute, 204 Craft Avenue, Room B705, Pittsburgh, PA, 15213, USA

    Adrian V. Lee

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  1. Angelo J. Casa
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Correspondence to Adrian V. Lee.

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Casa, A.J., Potter, A.S., Malik, S. et al. Estrogen and insulin-like growth factor-I (IGF-I) independently down-regulate critical repressors of breast cancer growth. Breast Cancer Res Treat 132, 61–73 (2012). https://doi.org/10.1007/s10549-011-1540-0

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  • DOI: https://doi.org/10.1007/s10549-011-1540-0

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