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      The role of the insulin-like growth factor-1 system in breast cancer

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          Abstract

          IGF-1 is a potent mitogen of major importance in the mammary gland. IGF-1 binding to the cognate receptor, IGF-1R, triggers a signaling cascade leading to proliferative and anti-apoptotic events. Although many of the relevant molecular pathways and intracellular cascades remain to be elucidated, a growing body of evidence points to the important role of the IGF-1 system in breast cancer development, progression and metastasis. IGF-1 is a point of convergence for major signaling pathways implicated in breast cancer growth. In this review, we provide an overview and concise update on the function and regulation of IGF-1 as well as the role it plays in breast malignancies.

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          Role of the insulin-like growth factor family in cancer development and progression.

          H Yu, T. Rohan (2000)
          The insulin-like growth factors (IGFs) are mitogens that play a pivotal role in regulating cell proliferation, differentiation, and apoptosis. The effects of IGFs are mediated through the IGF-I receptor, which is also involved in cell transformation induced by tumor virus proteins and oncogene products. Six IGF-binding proteins (IGFBPs) can inhibit or enhance the actions of IGFs. These opposing effects are determined by the structures of the binding proteins. The effects of IGFBPs on IGFs are regulated in part by IGFBP proteases. Laboratory studies have shown that IGFs exert strong mitogenic and antiapoptotic actions on various cancer cells. IGFs also act synergistically with other mitogenic growth factors and steroids and antagonize the effect of antiproliferative molecules on cancer growth. The role of IGFs in cancer is supported by epidemiologic studies, which have found that high levels of circulating IGF-I and low levels of IGFBP-3 are associated with increased risk of several common cancers, including those of the prostate, breast, colorectum, and lung. Evidence further suggests that certain lifestyles, such as one involving a high-energy diet, may increase IGF-I levels, a finding that is supported by animal experiments indicating that IGFs may abolish the inhibitory effect of energy restriction on cancer growth. Further investigation of the role of IGFs in linking high energy intake, increased cell proliferation, suppression of apoptosis, and increased cancer risk may provide new insights into the etiology of cancer and lead to new strategies for cancer prevention.
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            Mammary gland development.

            Hector Macias, Lindsay Hinck (2012)
            The mammary gland develops through several distinct stages. The first transpires in the embryo as the ectoderm forms a mammary line that resolves into placodes. Regulated by epithelial–mesenchymal interactions, the placodes descend into the underlying mesenchyme and produce the rudimentary ductal structure of the gland present at birth. Subsequent stages of development—pubertal growth, pregnancy, lactation, and involution—occur postnatally under the regulation of hormones. Puberty initiates branching morphogenesis, which requires growth hormone (GH) and estrogen, as well as insulin-like growth factor 1 (IGF1), to create a ductal tree that fills the fat pad. Upon pregnancy, the combined actions of progesterone and prolactin generate alveoli, which secrete milk during lactation. Lack of demand for milk at weaning initiates the process of involution whereby the gland is remodeled back to its prepregnancy state. These processes require numerous signaling pathways that have distinct regulatory functions at different stages of gland development. Signaling pathways also regulate a specialized subpopulation of mammary stem cells that fuel the dramatic changes in the gland occurring with each pregnancy. Our knowledge of mammary gland development and mammary stem cell biology has significantly contributed to our understanding of breast cancer and has advanced the discovery of therapies to treat this disease.
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              Insulin receptor isoform A, a newly recognized, high-affinity insulin-like growth factor II receptor in fetal and cancer cells.

              F Frasca, G Pandini, P. Scalia … (1999)
              Insulin-like growth factor II (IGF-II) is a peptide growth factor that is homologous to both insulin-like growth factor I (IGF-I) and insulin and plays an important role in embryonic development and carcinogenesis. IGF-II is believed to mediate its cellular signaling via the transmembrane tyrosine kinase type 1 insulin-like growth factor receptor (IGF-I-R), which is also the receptor for IGF-I. Earlier studies with both cultured cells and transgenic mice, however, have suggested that in the embryo the insulin receptor (IR) may also be a receptor for IGF-II. In most cells and tissues, IR binds IGF-II with relatively low affinity. The IR is expressed in two isoforms (IR-A and IR-B) differing by 12 amino acids due to the alternative splicing of exon 11. In the present study we found that IR-A but not IR-B bound IGF-II with an affinity close to that of insulin. Moreover, IGF-II bound to IR-A with an affinity equal to that of IGF-II binding to the IGF-I-R. Activation of IR-A by insulin led primarily to metabolic effects, whereas activation of IR-A by IGF-II led primarily to mitogenic effects. These differences in the biological effects of IR-A when activated by either IGF-II or insulin were associated with differential recruitment and activation of intracellular substrates. IR-A was preferentially expressed in fetal cells such as fetal fibroblasts, muscle, liver and kidney and had a relatively increased proportion of isoform A. IR-A expression was also increased in several tumors including those of the breast and colon. These data indicate, therefore, that there are two receptors for IGF-II, both IGF-I-R and IR-A. Further, they suggest that interaction of IGF-II with IR-A may play a role both in fetal growth and cancer biology.
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                Author and article information

                Contributors
                Panagiotis F Christopoulos: panutsoschr@hotmail.com
                Pavlos Msaouel: msaouel@gmail.com
                Michael Koutsilieris: mkoutsil@med.uoa.gr
                Journal
                Journal ID (nlm-ta): Mol Cancer
                Journal ID (iso-abbrev): Mol. Cancer
                Title: Molecular Cancer
                Publisher: BioMed Central (London )
                ISSN (Electronic): 1476-4598
                Publication date (Electronic): 15 February 2015
                Publication date PMC-release: 15 February 2015
                Publication date Collection: 2015
                Volume: 14
                Electronic Location Identifier: 43
                Affiliations
                [ ]Department of Experimental Physiology, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias Street, 11527 Goudi, Athens, Greece
                [ ]Department of Internal Medicine, Jacobi Medical Center, Albert Einstein College of Medicine, Bronx, NY USA
                Article
                Publisher ID: 291
                DOI: 10.1186/s12943-015-0291-7
                PMC ID: 4335664
                PubMed ID: 25743390
                SO-VID: 3dc47471-9d5c-4264-8e4e-9ab3b1baaaa9
                Copyright © © Christopoulos et al.; licensee BioMed Central. 2015
                License:

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                Date received : 17 July 2014
                Date accepted : 7 January 2015
                Categories
                Subject: Review
                Custom metadata
                issue-copyright-statement © The Author(s) 2015

                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: insulin-like growth factor-1 (igf-1),igf-1 receptor (igf-1r),igf-binding proteins (igfbps),igf-1 signaling,igf-1 regulation,estrogens,estrogen receptor (er),breast cancer,mammary tumorigenesis
                Data availability:
                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: insulin-like growth factor-1 (igf-1), igf-1 receptor (igf-1r), igf-binding proteins (igfbps), igf-1 signaling, igf-1 regulation, estrogens, estrogen receptor (er), breast cancer, mammary tumorigenesis

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