Skip to main content
SpringerLink
Log in

IGFBP-2 and −5: important regulators of normal and neoplastic mammary gland physiology

  • REVIEW
  • Published:
Journal of Cell Communication and Signaling Aims and scope

Abstract

The insulin-like growth factor (IGF) axis plays an important role in mammary gland physiology. In addition, dysregulation of this molecular axis may have a causal role in the aetiology and development of breast cancer (BC). This report discusses the IGF axis in normal and neoplastic mammary gland with special reference to IGF binding proteins (IGFBPs) -2 and −5. We describe how these high affinity binders of IGF-1 and IGF-2 may regulate local actions of growth factors in an autocrine and/or paracrine manner and how they also have IGF-independent effects in mammary gland. We discuss clinical studies which investigate both the prognostic value of IGFBP-2 and −5 expression in BC and possible involvement of these genes in the development of resistance to adjuvant endocrine therapies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  • Ahmed SR et al (1990) Characterization and hormonal regulation of radioimmunoassayable IGF-I (insulin-like growth factor I) like activity and IGF-binding proteins secreted by human breast cancer cells. Anticancer Res 10(5A):1217–1223

    CAS  PubMed  Google Scholar 

  • Ahn BY et al (2010) Genetic screen identifies insulin-like growth factor binding protein 5 as a modulator of tamoxifen resistance in breast cancer. Cancer Res 70(8):3013–3019

    Article  CAS  PubMed  Google Scholar 

  • Akkiprik M et al (2009) The subcellular localization of IGFBP5 affects its cell growth and migration functions in breast cancer. BMC Cancer 9:103

    Article  PubMed Central  PubMed  Google Scholar 

  • Allander SV et al (1994) Characterization of the chromosomal gene and promoter for human insulin-like growth factor binding protein-5. J Biol Chem 269(14):10891–10898

    CAS  PubMed  Google Scholar 

  • Amaar YG et al (2002) Insulin-like growth factor-binding protein 5 (IGFBP-5) interacts with a four and a half LIM protein 2 (FHL2). J Biol Chem 277(14):12053–12060

    Article  CAS  PubMed  Google Scholar 

  • Amaar YG, Baylink DJ, Mohan S (2005) Ras-association domain family 1 protein, RASSF1C, is an IGFBP-5 binding partner and a potential regulator of osteoblast cell proliferation. J Bone Miner Res 20(8):1430–1439

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Arai T et al (1994) Glycosaminoglycans inhibit degradation of insulin-like growth factor-binding protein-5. Endocrinology 135(6):2358–2363

    CAS  PubMed  Google Scholar 

  • Arteaga CL et al (1989) Blockade of the type I somatomedin receptor inhibits growth of human breast cancer cells in athymic mice. J Clin Invest 84(5):1418–1423

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Beattie J et al (2006) Insulin-like growth factor-binding protein-5 (IGFBP-5): a critical member of the IGF axis. Biochem J 395(1):1–19

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Becker MA et al (2012) IGFBP ratio confers resistance to IGF targeting and correlates with increased invasion and poor outcome in breast tumors. Clin Cancer Res 18(6):1808–1817

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Belfiore A, Frasca F (2008) IGF and insulin receptor signaling in breast cancer. J Mammary Gland Biol Neoplasia 13(4):381–406

    Article  PubMed  Google Scholar 

  • Boylan M, van den Berg HW, Lynch M (1998) The anti-proliferative effect of suramin towards tamoxifen-sensitive and resistant human breast cancer cell lines in relation to expression of receptors for epidermal growth factor and insulin-like growth factor-I: growth stimulation in the presence of tamoxifen. Ann Oncol 9(2):205–211

    Article  CAS  PubMed  Google Scholar 

  • Busund LT et al (2005) Significant expression of IGFBP2 in breast cancer compared with benign lesions. J Clin Pathol 58(4):361–366

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Butt AJ et al (2003) Insulin-like growth factor-binding protein-5 inhibits the growth of human breast cancer cells in vitro and in vivo. J Biol Chem 278(32):29676–29685

    Article  CAS  PubMed  Google Scholar 

  • Butt AJ et al (2005) Enhancement of tumor necrosis factor-alpha-induced growth inhibition by insulin-like growth factor-binding protein-5 (IGFBP-5), but not IGFBP-3 in human breast cancer cells. Endocrinology 146(7):3113–3122

    Article  CAS  PubMed  Google Scholar 

  • Cheng HL, Shy M, Feldman EL (1999) Regulation of insulin-like growth factor-binding protein-5 expression during Schwann cell differentiation. Endocrinology 140(10):4478–4485

    CAS  PubMed  Google Scholar 

  • Clarkson RW, Watson CJ (2003) Microarray analysis of the involution switch. J Mammary Gland Biol Neoplasia 8(3):309–319

    Article  PubMed  Google Scholar 

  • Clemmons DR (2007) Modifying IGF1 activity: an approach to treat endocrine disorders, atherosclerosis and cancer. Nat Rev Drug Discov 6(10):821–833

    Article  CAS  PubMed  Google Scholar 

  • Coutts A, Murphy LJ, Murphy LC (1994) Expression of insulin-like growth factor binding proteins by T-47D human breast cancer cells: regulation by progestins and antiestrogens. Breast Cancer Res Treat 32(2):153–164

    Article  CAS  PubMed  Google Scholar 

  • Cullen KJ et al (1992) Insulin-like growth factor expression in breast cancer epithelium and stroma. Breast Cancer Res Treat 22(1):21–29

    Article  CAS  PubMed  Google Scholar 

  • De Leon DD et al (1988) Demonstration of insulin-like growth factor (IGF-I and -II) receptors and binding protein in human breast cancer cell lines. Biochem Biophys Res Commun 152(1):398–405

    Article  PubMed  Google Scholar 

  • De Leon DD et al (1989) Characterization of insulin-like growth factor binding proteins from human breast cancer cells. Mol Endocrinol 3(3):567–574

    Article  PubMed  Google Scholar 

  • De Leon DD et al (1990) Insulin-like growth factor binding proteins in human breast cancer cells: relationship to hIGFBP-2 and hIGFBP-3. J Clin Endocrinol Metab 71(2):530–532

    Article  PubMed  Google Scholar 

  • Dean SJ et al (2014) Loss of PTEN expression is associated with IGFBP2 expression, younger age, and late stage in triple-negative breast cancer. Am J Clin Pathol 141(3):323–333

    Article  PubMed  Google Scholar 

  • Disis ML et al (2013) A multiantigen vaccine targeting neu, IGFBP-2, and IGF-IR prevents tumor progression in mice with preinvasive breast disease. Cancer Prev Res (Phila) 6(12):1273–1282

    Article  CAS  Google Scholar 

  • Dokmanovic M et al (2011) Trastuzumab regulates IGFBP-2 and IGFBP-3 to mediate growth inhibition: implications for the development of predictive biomarkers for trastuzumab resistance. Mol Cancer Ther 10(6):917–928

    Article  CAS  PubMed  Google Scholar 

  • Dubois V et al (1995) Intracellular levels and secretion of insulin-like-growth-factor-binding proteins in MCF-7/6, MCF-7/AZ and MDA-MB-231 breast cancer cells. differential modulation by estrogens in serum-free medium. Eur J Biochem 232(1):47–53

    Article  CAS  PubMed  Google Scholar 

  • Foulstone EJ et al (2013) Insulin-like growth factor binding protein 2 (IGFBP-2) promotes growth and survival of breast epithelial cells: novel regulation of the estrogen receptor. Endocrinology 154(5):1780–1793

    Article  CAS  PubMed  Google Scholar 

  • Frommer KW et al (2006) IGF-independent effects of IGFBP-2 on the human breast cancer cell line Hs578T. J Mol Endocrinol 37(1):13–23

    Article  CAS  PubMed  Google Scholar 

  • Garner CP et al (2008) Genetic variation in IGFBP2 and IGFBP5 is associated with breast cancer in populations of African descent. Hum Genet 123(3):247–255

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Ghoussaini M et al (2014) Evidence that breast cancer risk at the 2q35 locus is mediated through IGFBP5 regulation. Nat Commun 4:4999

    Article  PubMed  Google Scholar 

  • Hadsell DL, Baumrucker CR, Kensinger RS (1993) Effects of elevated blood insulin-like growth factor-I (IGF-I) concentration upon IGF-I in bovine mammary secretions during the colostrum phase. J Endocrinol 137(2):223–230

    Article  CAS  PubMed  Google Scholar 

  • Hao X et al (2004) Differential gene and protein expression in primary breast malignancies and their lymph node metastases as revealed by combined cDNA microarray and tissue microarray analysis. Cancer 100(6):1110–1122

    Article  CAS  PubMed  Google Scholar 

  • Huff KK et al (1986) Secretion of an insulin-like growth factor-I-related protein by human breast cancer cells. Cancer Res 46(9):4613–4619

    CAS  PubMed  Google Scholar 

  • Huynh H (1998) In vivo regulation of the insulin-like growth factor system of mitogens by human chorionic gonadotropin. Int J Oncol 13(3):571–575

    CAS  PubMed  Google Scholar 

  • Huynh H, Yang XF, Pollak M (1996) A role for insulin-like growth factor binding protein 5 in the antiproliferative action of the antiestrogen ICI 182780. Cell Growth Differ 7(11):1501–1506

    CAS  PubMed  Google Scholar 

  • Juncker-Jensen A et al (2006) Insulin-like growth factor binding protein 2 is a marker for antiestrogen resistant human breast cancer cell lines but is not a major growth regulator. Growth Horm IGF Res 16(4):224–239

    Article  CAS  PubMed  Google Scholar 

  • Knowlden JM et al (2005) Insulin-like growth factor-I receptor signaling in tamoxifen-resistant breast cancer: a supporting role to the epidermal growth factor receptor. Endocrinology 146(11):4609–4618

    Article  CAS  PubMed  Google Scholar 

  • Li X et al (2007) Expression level of insulin-like growth factor binding protein 5 mRNA is a prognostic factor for breast cancer. Cancer Sci 98(10):1592–1596

    Article  CAS  PubMed  Google Scholar 

  • Lochrie JD et al (2006) Insulin-like growth factor binding protein (IGFBP)-5 is upregulated during both differentiation and apoptosis in primary cultures of mouse mammary epithelial cells. J Cell Physiol 207(2):471–479

    Article  CAS  PubMed  Google Scholar 

  • Manni A et al (1994) Hormonal regulation of insulin-like growth factor II and insulin-like growth factor binding protein expression by breast cancer cells in vivo: evidence for stromal epithelial interactions. Cancer Res 54(11):2934–2942

    CAS  PubMed  Google Scholar 

  • Marshman E et al (2003) Insulin-like growth factor binding protein 5 and apoptosis in mammary epithelial cells. J Cell Sci 116(Pt 4):675–682

    Article  CAS  PubMed  Google Scholar 

  • Martin JL, Baxter RC (2007) Expression of insulin-like growth factor binding protein-2 by MCF-7 breast cancer cells is regulated through the phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin pathway. Endocrinology 148(5):2532–2541

    Article  CAS  PubMed  Google Scholar 

  • Massarweh S et al (2006) Mechanisms of tumor regression and resistance to estrogen deprivation and fulvestrant in a model of estrogen receptor-positive, HER-2/neu-positive breast cancer. Cancer Res 66(16):8266–8273

    Article  CAS  PubMed  Google Scholar 

  • Maxwell P, van den Berg HW (1999) Changes in the secretion of insulin-like growth factor binding proteins −2 and −4 associated with the development of tamoxifen resistance and estrogen independence in human breast cancer cell lines. Cancer Lett 139(2):121–127

    Article  CAS  PubMed  Google Scholar 

  • McCaig C, Perks CM, Holly JM (2002) Signalling pathways involved in the direct effects of IGFBP-5 on breast epithelial cell attachment and survival. J Cell Biochem 84(4):784–794

    Article  PubMed  Google Scholar 

  • McCotter D et al (1996) Changes in insulin-like growth factor-I receptor expression and binding protein secretion associated with tamoxifen resistance and estrogen independence in human breast cancer cells in vitro. Cancer Lett 99(2):239–245

    Article  CAS  PubMed  Google Scholar 

  • McGrath MF et al (1991) The direct in vitro effect of insulin-like growth factors (IGFs) on normal bovine mammary cell proliferation and production of IGF binding proteins. Endocrinology 129(2):671–678

    Article  CAS  PubMed  Google Scholar 

  • McGuire WL Jr et al (1992) Regulation of insulin-like growth factor-binding protein (IGFBP) expression by breast cancer cells: use of IGFBP-1 as an inhibitor of insulin-like growth factor action. J Natl Cancer Inst 84(17):1336–1341

    Article  CAS  PubMed  Google Scholar 

  • McGuire SE et al (1994) Detection of insulin-like growth factor binding proteins (IGFBPs) by ligand blotting in breast cancer tissues. Cancer Lett 77(1):25–32

    Article  CAS  PubMed  Google Scholar 

  • Minuto F et al (1987) Partial characterization of somatomedin C-like immunoreactivity secreted by breast cancer cells in vitro. Mol Cell Endocrinol 54(2–3):179–184

    Article  CAS  PubMed  Google Scholar 

  • Mireuta M, Darnel A, Pollak M (2010) IGFBP-2 expression in MCF-7 cells is regulated by the PI3K/AKT/mTOR pathway through Sp1-induced increase in transcription. Growth Factors 28(4):243–255

    Article  CAS  PubMed  Google Scholar 

  • Mita K et al (2007) Prognostic significance of insulin-like growth factor binding protein (IGFBP)-4 and IGFBP-5 expression in breast cancer. Jpn J Clin Oncol 37(8):575–582

    Article  PubMed  Google Scholar 

  • Osborne CK, Clemmons DR, Arteaga CL (1990) Regulation of breast cancer growth by insulin-like growth factors. J Steroid Biochem Mol Biol 37(6):805–809

    Article  CAS  PubMed  Google Scholar 

  • Parisot JP et al (1999a) Induction of insulin-like growth factor binding protein expression by ICI 182,780 in a tamoxifen-resistant human breast cancer cell line. Breast Cancer Res Treat 55(3):231–242

    Article  CAS  PubMed  Google Scholar 

  • Parisot JP et al (1999b) Altered expression of the IGF-1 receptor in a tamoxifen-resistant human breast cancer cell line. Br J Cancer 79(5–6):693–700

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Park KH et al (2008) Insulin-like growth factor-binding protein-2 is a target for the immunomodulation of breast cancer. Cancer Res 68(20):8400–8409

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Pekonen F et al (1992) Insulin-like growth factor binding proteins in human breast cancer tissue. Cancer Res 52(19):5204–5207

    CAS  PubMed  Google Scholar 

  • Pereira JJ et al (2004) Bimolecular interaction of insulin-like growth factor (IGF) binding protein-2 with alphavbeta3 negatively modulates IGF-I-mediated migration and tumor growth. Cancer Res 64(3):977–984

    Article  CAS  PubMed  Google Scholar 

  • Perks CM et al (1999) Differential IGF-independent effects of insulin-like growth factor binding proteins (1–6) on apoptosis of breast epithelial cells. J Cell Biochem 75(4):652–664

    Article  CAS  PubMed  Google Scholar 

  • Perks CM et al (2002) Effects of a non-IGF binding mutant of IGFBP-5 on cell death in human breast cancer cells. Biochem Biophys Res Commun 294(5):995–1000

    Article  CAS  PubMed  Google Scholar 

  • Perks CM et al (2007) IGF-II and IGFBP-2 differentially regulate PTEN in human breast cancer cells. Oncogene 26(40):5966–5972

    Article  CAS  PubMed  Google Scholar 

  • Phillips K et al (2003) Hormonal control of IGF-binding protein (IGFBP)-5 and IGFBP-2 secretion during differentiation of the HC11 mouse mammary epithelial cell line. J Mol Endocrinol 31(1):197–208

    Article  CAS  PubMed  Google Scholar 

  • Plant HC et al (2014) Differential subcellular and extracellular localisations of proteins required for insulin-like growth factor- and extracellular matrix-induced signalling events in breast cancer progression. BMC Cancer 14:627

    Article  PubMed Central  PubMed  Google Scholar 

  • Pollak MN (1998) Endocrine effects of IGF-I on normal and transformed breast epithelial cells: potential relevance to strategies for breast cancer treatment and prevention. Breast Cancer Res Treat 47(3):209–217

    Article  CAS  PubMed  Google Scholar 

  • Rotwein P, James PL, Kou K (1995) Rapid activation of insulin-like growth factor binding protein-5 gene transcription during myoblast differentiation. Mol Endocrinol 9(7):913–923

    CAS  PubMed  Google Scholar 

  • Rozen F, Pollak M (1999) Inhibition of insulin-like growth factor I receptor signaling by the vitamin D analogue EB1089 in MCF-7 breast cancer cells: A role for insulin-like growth factor binding proteins. Int J Oncol 15(3):589–594

    CAS  PubMed  Google Scholar 

  • Rudolph MC et al (2003) Functional development of the mammary gland: use of expression profiling and trajectory clustering to reveal changes in gene expression during pregnancy, lactation, and involution. J Mammary Gland Biol Neoplasia 8(3):287–307

    Article  PubMed  Google Scholar 

  • Schedlich LJ et al (1998) Insulin-like growth factor-binding protein (IGFBP)-3 and IGFBP-5 share a common nuclear transport pathway in T47D human breast carcinoma cells. J Biol Chem 273(29):18347–18352

    Article  CAS  PubMed  Google Scholar 

  • Schutt BS et al (2004) Integrin-mediated action of insulin-like growth factor binding protein-2 in tumor cells. J Mol Endocrinol 32(3):859–868

    Article  CAS  PubMed  Google Scholar 

  • Sehgal P et al (2013) Regulation of protumorigenic pathways by insulin like growth factor binding protein2 and its association along with beta-catenin in breast cancer lymph node metastasis. Mol Cancer 12:63

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Sheikh MS et al (1992) Identification of the insulin-like growth factor binding proteins 5 and 6 (IGFBP-5 and 6) in human breast cancer cells. Biochem Biophys Res Commun 183(3):1003–1010

    Article  CAS  PubMed  Google Scholar 

  • So AI et al (2008) Insulin-like growth factor binding protein-2 is a novel therapeutic target associated with breast cancer. Clin Cancer Res 14(21):6944–6954

    Article  CAS  PubMed  Google Scholar 

  • Soh, C.L., et al., Exogenous administration of protease-resistant, non-matrix-binding IGFBP-2 inhibits tumour growth in a murine model of breast cancer. Br J Cancer, 2014.

  • Sureshbabu A et al (2012) IGFBP5 induces cell adhesion, increases cell survival and inhibits cell migration in MCF-7 human breast cancer cells. J Cell Sci 125(Pt 7):1693–1705

    Article  CAS  PubMed  Google Scholar 

  • Taylor KJ et al (2010) Dynamic changes in gene expression in vivo predict prognosis of tamoxifen-treated patients with breast cancer. Breast Cancer Res 12(3):R39

    Article  PubMed Central  PubMed  Google Scholar 

  • Tonner E et al (1997) Hormonal control of insulin-like growth factor-binding protein-5 production in the involuting mammary gland of the rat. Endocrinology 138(12):5101–5107

    CAS  PubMed  Google Scholar 

  • Tonner E et al (2000) Insulin-like growth factor binding protein-5 (IGFBP-5) potentially regulates programmed cell death and plasminogen activation in the mammary gland. Adv Exp Med Biol 480:45–53

    CAS  PubMed  Google Scholar 

  • Tonner E et al (2002) Insulin-like growth factor binding protein-5 (IGFBP-5) induces premature cell death in the mammary glands of transgenic mice. Development 129(19):4547–4557

    CAS  PubMed  Google Scholar 

  • van den Berg HW et al (1996) Expression of receptors for epidermal growth factor and insulin-like growth factor I by ZR-75-1 human breast cancer cell variants is inversely related: the effect of steroid hormones on insulin-like growth factor I receptor expression. Br J Cancer 73(4):477–481

    Article  PubMed Central  PubMed  Google Scholar 

  • Vijayan A et al (2013) IGFBP-5 enhances epithelial cell adhesion and protects epithelial cells from TGFbeta1-induced mesenchymal invasion. Int J Biochem Cell Biol 45(12):2774–2785

    Article  CAS  PubMed  Google Scholar 

  • Wang H et al (2008) IGFBP2 and IGFBP5 overexpression correlates with the lymph node metastasis in T1 breast carcinomas. Breast J 14(3):261–267

    Article  PubMed  Google Scholar 

  • Wiseman LR et al (1993) Type I IGF receptor and acquired tamoxifen resistance in oestrogen-responsive human breast cancer cells. Eur J Cancer 29A(16):2256–2264

    Article  CAS  PubMed  Google Scholar 

  • Wood TL et al (2000) The insulin-like growth factors (IGFs) and IGF binding proteins in postnatal development of murine mammary glands. J Mammary Gland Biol Neoplasia 5(1):31–42

    Article  CAS  PubMed  Google Scholar 

  • Yamashita H et al (2009) Predictors of response to exemestane as primary endocrine therapy in estrogen receptor-positive breast cancer. Cancer Sci 100(11):2028–2033

    Article  CAS  PubMed  Google Scholar 

  • Yee D et al (1988) Insulin-like growth factor II mRNA expression in human breast cancer. Cancer Res 48(23):6691–6696

    CAS  PubMed  Google Scholar 

  • Yee D et al (1989) Analysis of insulin-like growth factor I gene expression in malignancy: evidence for a paracrine role in human breast cancer. Mol Endocrinol 3(3):509–517

    Article  CAS  PubMed  Google Scholar 

  • Zeng L, Holly JM, Perks CM (2014) Effects of physiological levels of the green tea extract epigallocatechin-3-gallate on breast cancer cells. Front Endocrinol (Lausanne) 5:61

    Google Scholar 

Download references

Acknowledgments

King Faisal Specialist Hospital & research Centre—Jeddah (KFSH&RC-Jed) YH, the King AbdulAziz University –Jeddah (KAAU) HA. RE acknowledges WELMEC, a Centre of Excellence in Medical Engineering funded by the Wellcome Trust and EPSRC, under grant number WT 088908/Z/09/Z for financial support. HA and YH acknowledge the Royal Embassy of Saudi Arabia – Cultural Bureau (UK) for financial support.

Author information

Authors and Affiliations

  1. Department of Oral Biology, School of Dentistry, St James University Hospital, Level 7, Wellcome Trust Brenner Building, Leeds, LS9 7TF, UK

    James Beattie, Yousef Hawsawi, Hanaa Alkharobi & Reem El-Gendy

Authors
  1. James Beattie
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yousef Hawsawi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hanaa Alkharobi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Reem El-Gendy
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to James Beattie.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Beattie, J., Hawsawi, Y., Alkharobi, H. et al. IGFBP-2 and −5: important regulators of normal and neoplastic mammary gland physiology. J. Cell Commun. Signal. 9, 151–158 (2015). https://doi.org/10.1007/s12079-015-0260-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12079-015-0260-3

Keywords

Search

Navigation