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IGF Binding Proteins (IGFBPs) and Regulation of Breast Cancer Biology

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Journal of Mammary Gland Biology and Neoplasia Aims and scope Submit manuscript

Abstract

The IGFBP family comprises six proteins with high affinity for the IGFs. Changes in the balance of the components of the IGF system may contribute to the progression of breast cancer. In tumours the abundance of IGFBPs relates to the estrogen receptor status and their production in the breast is controlled by hormones, principally estrogen and progesterone. Important interactions occur between IGFBPs and key growth regulators such as TGF-beta, PTEN and EGF which are reviewed. The conflicting observations between the effects of IGFBPs on the risk of breast cancer, in particular IGFBP-3, obtained from epidemiology studies in comparison to in vivo observations are highlighted and potential explanations provided. The functional activity of IGFBPs can also be affected by proteolysis, phosphorylation and glycosylation and the implications of these are described. The IGFs are generally present at levels far in excess of that required for maximal receptor stimulation, and the IGFBPs are critical regulators of their cellular actions. IGFBPs can affect cell function in an IGF-dependent or independent manner. The key mechanisms underlying the intrinsic actions of the IGFBPs are still in debate. IGF bioactivity locally in the breast is influenced not only by local tissue expression and regulation of IGFs, IGFBPs and IGFBP proteases, but also by these factors delivered from the circulation. Finally, the therapeutic potential of IGFBPs-2 and -3 are considered together with key questions that still need to be addressed.

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Abbreviations

IGF:

insulin-like growth factor

IGFBP:

insulin-like growth factor binding protein

DCIS:

ductal carcinomas in situ

ER:

estrogen receptor

SNPs:

single nucleotide polymorphisms

EGF-R:

epidermal growth factor receptor

PTEN:

dual-function phosphatase and tensin homolog deleted on chromosome 10

hks:

human kallikreins

PSA:

prostate-specific antigen

UPAS:

urokinase type plasmin activator system

RXR:

retinoid X receptor

PR:

progesterone receptor

References

  1. Baxter RC. IGF binding protein-3 and the acid-labile subunit: formation of the ternary complex in vitro and in vivo. Adv Exp Med Biol. 1993;343:237–44.

    PubMed  CAS  Google Scholar 

  2. Twigg SM, Baxter RC. Insulin-like growth factor (IGF)-binding protein 5 forms an alternative ternary complex with IGFs and the acid-labile subunit. J Biol Chem. 1998;273(11):6074–9. doi:10.1074/jbc.273.11.6074.

    PubMed  CAS  Google Scholar 

  3. Figueroa JA, Jackson JG, McGuire WL, Krywicki RF, Yee D. Expression of insulin-like growth factor binding proteins in human breast cancer correlates with estrogen receptor status. J Cell Biochem. 1993;52(2):196–205. doi:10.1002/jcb.240520211.

    PubMed  CAS  Google Scholar 

  4. Chen JC, Shao ZM, Sheikh MS, Hussain A, LeRoith D, Roberts CT Jr, et al. Insulin-like growth factor-binding protein enhancement of insulin-like growth factor-I (IGF-I)-mediated DNA synthesis and IGF-I binding in a human breast carcinoma cell line. J Cell Physiol. 1994;158(1):69–78. doi:10.1002/jcp.1041580110.

    PubMed  CAS  Google Scholar 

  5. Ritvos O, Ranta T, Jalkanen J, Suikkari AM, Voutilainen R, Bohn H, et al. Insulin-like growth factor (IGF) binding protein from human decidua inhibits the binding and biological action of IGF-I in cultured choriocarcinoma cells. Endocrinology. 1988;122(5):2150–7.

    PubMed  CAS  Google Scholar 

  6. Yee D, Favoni RE, Lippman ME, Powell DR. Identification of insulin-like growth factor binding proteins in breast cancer cells. Breast Cancer Res Treat. 1991;18(1):3–10. doi:10.1007/BF01975437.

    PubMed  CAS  Google Scholar 

  7. Clemmons DR, Camacho-Hubner C, Coronado E, Osborne CK. Insulin-like growth factor binding protein secretion by breast carcinoma cell lines: correlation with estrogen receptor status. Endocrinology. 1990;127(6):2679–86.

    PubMed  CAS  Google Scholar 

  8. Sheikh MS, Shao ZM, Clemmons DR, LeRoith D, Roberts CT Jr, Fontana JA. 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. 1992;183(3):1003–10. doi:10.1016/S0006-291X(05)80290-6.

    PubMed  CAS  Google Scholar 

  9. Pekonen F, Nyman T, Ilvesmaki V, Partanen S. Insulin-like growth factor binding proteins in human breast cancer tissue. Cancer Res. 1992;52(19):5204–7.

    PubMed  CAS  Google Scholar 

  10. Rocha RL, Hilsenbeck SG, Jackson JG, VanDenBerg CL, Weng C, Lee AV, et al. Insulin-like growth factor binding protein-3 and insulin receptor substrate-1 in breast cancer: correlation with clinical parameters and disease-free survival. Clin Cancer Res. 1997;3(1):103–9.

    PubMed  CAS  Google Scholar 

  11. Rocha RL, Hilsenbeck SG, Jackson JG, Lee AV, Figueroa JA, Yee D. Correlation of insulin-like growth factor-binding protein-3 messenger RNA with protein expression in primary breast cancer tissues: detection of higher levels in tumors with poor prognostic features. J Natl Cancer Inst. 1996;88(9):601–6. doi:10.1093/jnci/88.9.601.

    PubMed  CAS  Google Scholar 

  12. Yu H, Levesque MA, Khosravi MJ, Papanastasiou-Diamandi A, Clark GM, Diamandis EP. Associations between insulin-like growth factors and their binding proteins and other prognostic indicators in breast cancer. Br J Cancer. 1996;74(8):1242–7.

    PubMed  CAS  Google Scholar 

  13. Vestey S, Perks C, Sen C, Calder C, Holly J, Winters Z. Immunohistochemical expression of insulin-like growth factor binding protein-3 in invasive breast cancers and DCIS—implications for clinicopathology and patient outcome. Breast Cancer Res. 2004;7:R119–29. doi:10.1186/bcr963.

    PubMed  Google Scholar 

  14. Li X, Cao X, Li X, Zhang W, Feng Y. Expression level of insulin-like growth factor binding protein 5 mRNA is a prognostic factor for breast cancer. Cancer Sci. 2007;98(10):1592–6. doi:10.1111/j.1349-7006.2007.00565.x.

    PubMed  CAS  Google Scholar 

  15. Wang H, Arun BK, Wang H, Fuller GN, Zhang W, Middleton LP, et al. IGFBP2 and IGFBP5 overexpression correlates with the lymph node metastasis in T1 breast carcinomas. Breast J. 2008;14(3):261–7. doi:10.1111/j.1524-4741.2008.00572.x.

    PubMed  Google Scholar 

  16. Busund LT, Richardsen E, Busund R, Ukkonen T, Bjornsen T, Busch C, et al. Significant expression of IGFBP2 in breast cancer compared with benign lesions. J Clin Pathol. 2005;58(4):361–6. doi:10.1136/jcp.2004.020834.

    PubMed  CAS  Google Scholar 

  17. Yee D, Sharma J, Hilsenbeck SG. Prognostic significance of insulin-like growth factor-binding protein expression in axillary lymph node-negative breast cancer. J Natl Cancer Inst. 1994;86(23):1785–9. doi:10.1093/jnci/86.23.1785.

    PubMed  CAS  Google Scholar 

  18. Mita K, Zhang Z, Ando Y, Toyama T, Hamaguchi M, Kobayashi S, et al. Prognostic significance of insulin-like growth factor binding protein (IGFBP)-4 and IGFBP-5 expression in breast cancer. Jpn J Clin Oncol. 2007;37(8):575–82. doi:10.1093/jjco/hym066.

    PubMed  Google Scholar 

  19. Bohlke K, Cramer DW, Trichopoulos D, Mantzoros CS. Insulin-like growth factor-I in relation to premenopausal ductal carcinoma in situ of the breast. Epidemiology. 1998;9(5):570–3. doi:10.1097/00001648-199809000-00018.

    PubMed  CAS  Google Scholar 

  20. Bruning PF, Van Doorn J, Bonfrer JM, Van Noord PA, Korse CM, Linders TC, et al. Insulin-like growth-factor-binding protein 3 is decreased in early-stage operable pre-menopausal breast cancer. Int J Cancer. 1995;62(3):266–70. doi:10.1002/ijc.2910620306.

    PubMed  CAS  Google Scholar 

  21. Hankinson SE, Willett WC, Colditz GA, Hunter DJ, Michaud DS, Deroo B, et al. Circulating concentrations of insulin-like growth factor-I and risk of breast cancer. Lancet. 1998;351(9113):1393–6. doi:10.1016/S0140-6736(97)10384-1.

    PubMed  CAS  Google Scholar 

  22. Schernhammer ES, Holly JM, Pollak MN, Hankinson SE. Circulating levels of insulin-like growth factors, their binding proteins, and breast cancer risk. Cancer Epidemiol Biomarkers Prev. 2005;14(3):699–704. doi:10.1158/1055-9965.EPI-04-0561.

    PubMed  CAS  Google Scholar 

  23. Keinan-Boker L, Bueno De Mesquita HB, Kaaks R, Van Gils CH, Van Noord PA, Rinaldi S, et al. Circulating levels of insulin-like growth factor I, its binding proteins -1,-2, -3, C-peptide and risk of postmenopausal breast cancer. Int J Cancer. 2003;106(1):90–5. doi:10.1002/ijc.11193.

    PubMed  CAS  Google Scholar 

  24. Gronbaek H, Flyvbjerg A, Mellemkjaer L, Tjonneland A, Christensen J, Sorensen HT, et al. Serum insulin-like growth factors, insulin-like growth factor binding proteins, and breast cancer risk in postmenopausal women. Cancer Epidemiol Biomarkers Prev. 2004;13(11 Pt 1):1759–64.

    PubMed  CAS  Google Scholar 

  25. Kaulsay KK, Ng EH, Ji CY, Ho GH, Aw TC, Lee KO. Serum IGF-binding protein-6 and prostate specific antigen in breast cancer. Eur J Endocrinol. 1999;140(2):164–8. doi:10.1530/eje.0.1400164.

    PubMed  CAS  Google Scholar 

  26. Renehan AG, Zwahlen M, Minder C, O’Dwyer ST, Shalet SM, Egger M. Insulin-like growth factor (IGF)-I, IGF binding protein-3, and cancer risk: systematic review and meta-regression analysis. Lancet. 2004;363(9418):1346–53. doi:10.1016/S0140-6736(04)16044-3.

    PubMed  CAS  Google Scholar 

  27. McCaig C, Perks CM, Holly JM. Intrinsic actions of IGFBP-3 and IGFBP-5 on Hs578T breast cancer epithelial cells: inhibition or accentuation of attachment and survival is dependent upon the presence of fibronectin. J Cell Sci. 2002;115(Pt 22):4293–303. doi:10.1242/jcs.00097.

    PubMed  CAS  Google Scholar 

  28. Al-Zahrani A, Sandhu MS, Luben RN, Thompson D, Baynes C, Pooley KA, et al. IGF1 and IGFBP3 tagging polymorphisms are associated with circulating levels of IGF1, IGFBP3 and risk of breast cancer. Hum Mol Genet. 2006;15(1):1–10. doi:10.1093/hmg/ddi398.

    PubMed  CAS  Google Scholar 

  29. Ren Z, Cai Q, Shu XO, Cai H, Li C, Yu H, et al. Genetic polymorphisms in the IGFBP3 gene: association with breast cancer risk and blood IGFBP-3 protein levels among Chinese women. Cancer Epidemiol Biomarkers Prev. 2004;13(8):1290–5.

    PubMed  CAS  Google Scholar 

  30. Slattery ML, Sweeney C, Wolff R, Herrick J, Baumgartner K, Giuliano A, et al. Genetic variation in IGF1, IGFBP3, IRS1, IRS2 and risk of breast cancer in women living in Southwestern United States. Breast Cancer Res Treat. 2007;104(2):197–209. doi:10.1007/s10549-006-9403-9.

    PubMed  CAS  Google Scholar 

  31. Wagner K, Hemminki K, Israelsson E, Grzybowska E, Soderberg M, Pamula J, et al. Polymorphisms in the IGF-1 and IGFBP 3 promoter and the risk of breast cancer. Breast Cancer Res Treat. 2005;92(2):133–40. doi:10.1007/s10549-005-2417-x.

    PubMed  CAS  Google Scholar 

  32. Canzian F, McKay JD, Cleveland RJ, Dossus L, Biessy C, Rinaldi S, et al. Polymorphisms of genes coding for insulin-like growth factor 1 and its major binding proteins, circulating levels of IGF-I and IGFBP-3 and breast cancer risk: results from the EPIC study. Br J Cancer. 2006;94(2):299–307. doi:10.1038/sj.bjc.6602936.

    PubMed  CAS  Google Scholar 

  33. Cheng I, Penney KL, Stram DO, Le Marchand L, Giorgi E, Haiman CA, et al. Haplotype-based association studies of IGFBP1 and IGFBP3 with prostate and breast cancer risk: the multiethnic cohort. Cancer Epidemiol Biomarkers Prev. 2006;15(10):1993–7. doi:10.1158/1055-9965.EPI-06-0361.

    PubMed  CAS  Google Scholar 

  34. Schernhammer ES, Hankinson SE, Hunter DJ, Blouin MJ, Pollak MN. Polymorphic variation at the -202 locus in IGFBP3: influence on serum levels of insulin-like growth factors, interaction with plasma retinol and vitamin D and breast cancer risk. Int J Cancer. 2003;107(1):60–4. doi:10.1002/ijc.11358.

    PubMed  CAS  Google Scholar 

  35. Sigurdson AJ, Hauptmann M, Chatterjee N, Alexander BH, Doody MM, Rutter JL, et al. Kin-cohort estimates for familial breast cancer risk in relation to variants in DNA base excision repair, BRCA1 interacting and growth factor genes. BMC Cancer. 2004;4:9. doi:10.1186/1471-2407-4-9.

    PubMed  Google Scholar 

  36. Garner CP, Ding YC, John EM, Ingles SA, Olopade OI, Huo D, et al. Genetic variation in IGFBP2 and IGFBP5 is associated with breast cancer in populations of African descent. Hum Genet. 2008;123(3):247–55. doi:10.1007/s00439-008-0468-x.

    PubMed  CAS  Google Scholar 

  37. Boyd NF, Rommens JM, Vogt K, Lee V, Hopper JL, Yaffe MJ, et al. Mammographic breast density as an intermediate phenotype for breast cancer. Lancet Oncol. 2005;6(10):798–808. doi:10.1016/S1470-2045(05)70390-9.

    PubMed  Google Scholar 

  38. Lai JH, Vesprini D, Zhang W, Yaffe MJ, Pollak M, Narod SA. A polymorphic locus in the promoter region of the IGFBP3 gene is related to mammographic breast density. Cancer Epidemiol Biomarkers Prev. 2004;13(4):573–82.

    PubMed  CAS  Google Scholar 

  39. dos Santos Silva I, Johnson N, De Stavola B, Torres-Mejia G, Fletcher O, Allen DS, et al. The insulin-like growth factor system and mammographic features in premenopausal and postmenopausal women. Cancer Epidemiol Biomarkers Prev. 2006;15(3):449–55. doi:10.1158/1055-9965.EPI-05-0555.

    PubMed  CAS  Google Scholar 

  40. Tamimi RM, Cox DG, Kraft P, Pollak MN, Haiman CA, Cheng I, et al. Common genetic variation in IGF1, IGFBP-1, and IGFBP-3 in relation to mammographic density: a cross-sectional study. Breast Cancer Res. 2007;9(1):R18. doi:10.1186/bcr1655.

    PubMed  Google Scholar 

  41. Diorio C, Brisson J, Berube S, Pollak M. Genetic polymorphisms involved in insulin-like growth factor (IGF) pathway in relation to mammographic breast density and IGF levels. Cancer Epidemiol Biomarkers Prev. 2008;17(4):880–8. doi:10.1158/1055-9965.EPI-07-2500.

    PubMed  CAS  Google Scholar 

  42. Stewart AJ, Johnson MD, May FE, Westley BR. Role of insulin-like growth factors and the type I insulin-like growth factor receptor in the estrogen-stimulated proliferation of human breast cancer cells. J Biol Chem. 1990;265(34):21172–8.

    PubMed  CAS  Google Scholar 

  43. Lee AV, Darbre P, King RJ. Processing of insulin-like growth factor-II (IGF-II) by human breast cancer cells. Mol Cell Endocrinol. 1994;99(2):211–20. doi:10.1016/0303-7207(94)90010-8.

    PubMed  CAS  Google Scholar 

  44. Owens PC, Gill PG, De Young NJ, Weger MA, Knowles SE, Moyse KJ. Estrogen and progesterone regulate secretion of insulin-like growth factor binding proteins by human breast cancer cells. Biochem Biophys Res Commun. 1993;193(2):467–73. doi:10.1006/bbrc.1993.1647.

    PubMed  CAS  Google Scholar 

  45. Pratt SE, Pollak MN. Estrogen and antiestrogen modulation of MCF7 human breast cancer cell proliferation is associated with specific alterations in accumulation of insulin-like growth factor-binding proteins in conditioned media. Cancer Res. 1993;53(21):5193–8.

    PubMed  CAS  Google Scholar 

  46. Vignon F, Bardon S, Chalbos D, Rochefort H. Antiestrogenic effect of R5020, a synthetic progestin in human breast cancer cells in culture. J Clin Endocrinol Metab. 1993;56:1124–30.

    Google Scholar 

  47. Parisot JP, Leeding KS, Hu XF, DeLuise M, Zalcberg JR, Bach LA. 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. 1999;55(3):231–42. doi:10.1023/A:1006274712664.

    PubMed  CAS  Google Scholar 

  48. Milewicz T, Gregoraszczuk EL, Sztefko K, Augustowska K, Krzysiek J, Rys J. Lack of synergy between estrogen and progesterone on local IGF-I, IGFBP-3 and IGFBP-2 secretion by both hormone-dependent and hormone-independent breast cancer explants in vitro. Effect of tamoxifen and mifepristone (RU 486). Growth Horm IGF Res. 2005;15(2):140–7. doi:10.1016/j.ghir.2004.12.006.

    PubMed  CAS  Google Scholar 

  49. Juncker-Jensen A, Lykkesfeldt AE, Worm J, Ralfkiaer U, Espelund U, Jepsen JS. 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. 2006;16(4):224–39. doi:10.1016/j.ghir.2006.06.005.

    PubMed  CAS  Google Scholar 

  50. Lonning E, Lien EA. Mechanisms of action of endocrine treatment in breast cancer. Crit Rev Oncol Hematol. 1995;21(1–3):158–93. doi:10.1016/1040-8428(94)00172-3.

    PubMed  CAS  Google Scholar 

  51. Lonning PE, Hall K, Aakvaag A, Lien EA. Influence of tamoxifen on plasma levels of insulin-like growth factor I and insulin-like growth factor binding protein I in breast cancer patients. Cancer Res. 1992;52(17):4719–23.

    PubMed  CAS  Google Scholar 

  52. Pollak MN, Huynh HT, Lefebvre SP. Tamoxifen reduces serum insulin-like growth factor I (IGF-I). Breast Cancer Res Treat. 1992;22(1):91–100. doi:10.1007/BF01833337.

    PubMed  CAS  Google Scholar 

  53. Gronbaek H, Tanos V, Meirow D, Peretz T, Raz I, Flyvbjerg A. Effects of tamoxifen on insulin-like growth factors, IGF binding proteins and IGFBP-3 proteolysis in breast cancer patients. Anticancer Res. 2003;23(3C):2815–20.

    PubMed  Google Scholar 

  54. Helle SI, Holly JM, Tally M, Hall K, Vander Stappen J, Lonning PE. Influence of treatment with tamoxifen and change in tumor burden on the IGF-system in breast cancer patients. Int J Cancer. 1996;69(4):335–9. doi:10.1002/(SICI)1097-0215(19960822)69:4<335::AID-IJC17>3.0.CO;2-4.

    PubMed  CAS  Google Scholar 

  55. Helle SI, Mietlowski W, Guastalla JP, Szakolczai I, Bajetta E, Sommer H, et al. Effects of tamoxifen and octreotide LAR on the IGF-system compared with tamoxifen monotherapy. Eur J Cancer. 2005;41(5):694–701. doi:10.1016/j.ejca.2004.12.015.

    PubMed  CAS  Google Scholar 

  56. Lawrence JB, Conover CA, Haddad TC, Ingle JN, Reid JM, Ames MM, et al. Evaluation of continuous infusion suramin in metastatic breast cancer: impact on plasma levels of insulin-like growth factors (IGFs) and IGF-binding proteins. Clin Cancer Res. 1997;3(10):1713–20.

    PubMed  CAS  Google Scholar 

  57. Lien EA, Johannessen DC, Aakvaag A, Lonning PE. Influence of tamoxifen, aminoglutethimide and goserelin on human plasma IGF-I levels in breast cancer patients. J Steroid Biochem Mol Biol 1992;41(3–8):541–3.

    PubMed  CAS  Google Scholar 

  58. Bajetta E, Ferrari L, Celio L, Mariani L, Miceli R, Di Leo A, et al. The aromatase inhibitor letrozole in advanced breast cancer: effects on serum insulin-like growth factor (IGF)-I and IGF-binding protein-3 levels. J Steroid Biochem Mol Biol. 1997;63(4–6):261–7. doi:10.1016/S0960-0760(97)00120-9.

    PubMed  CAS  Google Scholar 

  59. Reed MJ, Christodoulides A, Koistinen R, Seppala M, Teale JD, Ghilchik MW. The effect of endocrine therapy with medroxyprogesterone acetate, 4-hydroxyandrostenedione or tamoxifen on plasma concentrations of insulin-like growth factor (IGF)-I, IGF-II and IGFBP-1 in women with advanced breast cancer. Int J Cancer. 1992;52(2):208–12. doi:10.1002/ijc.2910520209.

    PubMed  CAS  Google Scholar 

  60. Helle SI, Jonat W, Giurescu M, Ekse D, Holly JM, Lonning PE. Influence of treatment with onapristone on the IGF-system in breast cancer patients. J Steroid Biochem Mol Biol. 1998;66(3):159–63. doi:10.1016/S0960-0760(98)00046-6.

    PubMed  CAS  Google Scholar 

  61. Frost VJ, Helle SI, Lonning PE, van der Stappen JW, Holly JM. Effects of treatment with megestrol acetate, aminoglutethimide, or formestane on insulin-like growth factor (IGF) I and II, IGF-binding proteins (IGFBPs), and IGFBP-3 protease status in patients with advanced breast cancer. J Clin Endocrinol Metab. 1996;81(6):2216–21. doi:10.1210/jc.81.6.2216.

    PubMed  CAS  Google Scholar 

  62. Perks CM, Holly JM. IGFBPs and breast cancer. Breast Dis. 2003;17:91–104.

    PubMed  CAS  Google Scholar 

  63. James SY, Mackay AG, Colston KW. Effects of 1,25 dihydroxyvitamin D3 and its analogues on induction of apoptosis in breast cancer cells. J Steroid Biochem Mol Biol. 1996;58(4):395–401. doi:10.1016/0960-0760(96)00048-9.

    PubMed  CAS  Google Scholar 

  64. Towsend K, Trevino V, Falciani F, Stewart PM, Hewison M, Campbell MJ. Identification of VDR-responsive gene signatures in breast cancer cells. Oncology. 2006;71(1–2):111–23. doi:10.1159/000100989.

    PubMed  CAS  Google Scholar 

  65. Danforth DN Jr, Sgagias MK. Tumor necrosis factor alpha enhances secretion of transforming growth factor beta2 in MCF-7 breast cancer cells. Clin Cancer Res. 1996;2(5):827–35.

    PubMed  CAS  Google Scholar 

  66. Koli K, Keski-Oja J. 1,25-Dihydroxyvitamin D3 enhances the expression of transforming growth factor beta 1 and its latent form binding protein in cultured breast carcinoma cells. Cancer Res. 1995;55(7):1540–6.

    PubMed  CAS  Google Scholar 

  67. Mirza MR. Anti-estrogen induced synthesis of transforming growth factor-beta in breast cancer patients. Cancer Treat Rev. 1991;18(2):145–8. doi:10.1016/0305-7372(91)90011-N.

    PubMed  CAS  Google Scholar 

  68. Lai LC, Erbas H, Meadows KA, Lennard TW, Holly JM. Insulin-like growth factor binding protein-3 in breast cyst fluid: relationships with insulin-like growth factors I and II and transforming growth factor-beta 1 and 2. Cancer Lett. 1996;110(1–2):207–12. doi:10.1016/S0304-3835(96)04497-7.

    PubMed  CAS  Google Scholar 

  69. McCaig C, Fowler CA, Laurence NJ, Lai T, Savage PB, Holly JM, et al. Differential interactions between IGFBP-3 and transforming growth factor-beta (TGF-beta) in normal vs cancerous breast epithelial cells. Br J Cancer. 2002;86(12):1963–9. doi:10.1038/sj.bjc.6600355.

    PubMed  CAS  Google Scholar 

  70. Salahifar H, Baxter RC, Martin JL. Differential regulation of insulin-like growth factor-binding protein-3 protease activity in MCF-7 breast cancer cells by estrogen and transforming growth factor-beta1. Endocrinology. 2000;141(9):3104–10. doi:10.1210/en.141.9.3104.

    PubMed  CAS  Google Scholar 

  71. Martin JL, Weenink SM, Baxter RC. Insulin-like growth factor-binding protein-3 potentiates epidermal growth factor action in MCF-10A mammary epithelial cells. Involvement of p44/42 and p38 mitogen-activated protein kinases. J Biol Chem. 2003;278(5):2969–76. doi:10.1074/jbc.M210739200.

    PubMed  CAS  Google Scholar 

  72. Butt AJ, Martin JL, Dickson KA, McDougall F, Firth SM, Baxter RC. Insulin-like growth factor binding protein-3 expression is associated with growth stimulation of T47D human breast cancer cells: the role of altered epidermal growth factor signaling. J Clin Endocrinol Metab. 2004;89(4):1950–6. doi:10.1210/jc.2003-030914.

    PubMed  CAS  Google Scholar 

  73. Guix M, Faber AC, Wang SE, Olivares MG, Song Y, Qu S, et al. Acquired resistance to EGFR tyrosine kinase inhibitors in cancer cells is mediated by loss of IGF-binding proteins. J Clin Invest. 2008;118(7):2609–19.

    PubMed  CAS  Google Scholar 

  74. Moorehead RA, Hojilla CV, De Belle I, Wood GA, Fata JE, Adamson ED, et al. Insulin-like growth factor-II regulates PTEN expression in the mammary gland. J Biol Chem. 2003;278(50):50422–7. doi:10.1074/jbc.M306894200.

    PubMed  CAS  Google Scholar 

  75. Perks CM, Vernon EG, Rosendahl AH, Tonge D, Holly JM. IGF-II and IGFBP-2 differentially regulate PTEN in human breast cancer cells. Oncogene. 2007;26(40):5966–72. doi:10.1038/sj.onc.1210397.

    PubMed  CAS  Google Scholar 

  76. Mehrian-Shai R, Chen CD, Shi T, Horvath S, Nelson SF, Reichardt JK, et al. Insulin growth factor-binding protein 2 is a candidate biomarker for PTEN status and PI3K/Akt pathway activation in glioblastoma and prostate cancer. Proc Natl Acad Sci U S A. 2007;104(13):5563–8. doi:10.1073/pnas.0609139104.

    PubMed  CAS  Google Scholar 

  77. Frommer KW, Reichenmiller K, Schutt BS, Hoeflich A, Ranke MB, Dodt G, et al. IGF-independent effects of IGFBP-2 on the human breast cancer cell line Hs578T. J Mol Endocrinol. 2006;37(1):13–23. doi:10.1677/jme.1.01955.

    PubMed  CAS  Google Scholar 

  78. Lawrence JB, Oxvig C, Overgaard MT, Sottrup-Jensen L, Gleich GJ, Hays LG, et al. The insulin-like growth factor (IGF)-dependent IGF binding protein-4 protease secreted by human fibroblasts is pregnancy-associated plasma protein-A. Proc Natl Acad Sci U S A. 1999;96(6):3149–53. doi:10.1073/pnas.96.6.3149.

    PubMed  CAS  Google Scholar 

  79. Busby WH Jr, Nam TJ, Moralez A, Smith C, Jennings M, Clemmons DR. The complement component C1s is the protease that accounts for cleavage of insulin-like growth factor-binding protein-5 in fibroblast medium. J Biol Chem. 2000;275(48):37638–44. doi:10.1074/jbc.M006107200.

    PubMed  CAS  Google Scholar 

  80. Mohan S, Thompson GR, Amaar YG, Hathaway G, Tschesche H, Baylink DJ. ADAM-9 is an insulin-like growth factor binding protein-5 protease produced and secreted by human osteoblasts. Biochemistry. 2002;41(51):15394–403. doi:10.1021/bi026458q.

    PubMed  CAS  Google Scholar 

  81. Overgaard MT, Boldt HB, Laursen LS, Sottrup-Jensen L, Conover CA, Oxvig C. Pregnancy-associated plasma protein-A2 (PAPP-A2), a novel insulin-like growth factor-binding protein-5 proteinase. J Biol Chem. 2001;276(24):21849–53. doi:10.1074/jbc.M102191200.

    PubMed  CAS  Google Scholar 

  82. Hsieh ML, Charlesworth MC, Goodmanson M, Zhang S, Seay T, Klee GG, et al. Expression of human prostate-specific glandular kallikrein protein (hK2) in the breast cancer cell line T47-D. Cancer Res. 1997;57(13):2651–6.

    PubMed  CAS  Google Scholar 

  83. Magklara A, Scorilas A, Lopez-Otin C, Vizoso F, Ruibal A, Diamandis EP. Human glandular kallikrein in breast milk, amniotic fluid, and breast cyst fluid. Clin Chem. 1999;45(10):1774–80.

    PubMed  CAS  Google Scholar 

  84. Diamandis EP. Prostate specific antigen—new applications in breast and other cancers. Anticancer Res. 1996;16(6C):3983–4.

    PubMed  CAS  Google Scholar 

  85. Yu H, Diamandis EP, Levesque M, Giai M, Roagna R, Ponzone R, et al. Prostate specific antigen in breast cancer, benign breast disease and normal breast tissue. Breast Cancer Res Treat. 1996;40(2):171–8. doi:10.1007/BF01806212.

    PubMed  CAS  Google Scholar 

  86. Paliouras M, Diamandis EP. Coordinated steroid hormone-dependent and independent expression of multiple kallikreins in breast cancer cell lines. Breast Cancer Res Treat. 2007;102(1):7–18. doi:10.1007/s10549-006-9312-y.

    PubMed  CAS  Google Scholar 

  87. Paliouras M, Diamandis EP. Intracellular signaling pathways regulate hormone-dependent kallikrein gene expression. Tumour Biol. 2008;29(2):63–75. doi:10.1159/000135686.

    PubMed  CAS  Google Scholar 

  88. Ewan King L, Li X, Cheikh Saad Bouh K, Pedneault M, Chu CW. Human kallikrein 10 ELISA development and validation in breast cancer sera. Clin Biochem. 2007;40(13–14):1057–62. doi:10.1016/j.clinbiochem.2007.05.008.

    PubMed  Google Scholar 

  89. Rehault S, Monget P, Mazerbourg S, Tremblay R, Gutman N, Gauthier F, et al. Insulin-like growth factor binding proteins (IGFBPs) as potential physiological substrates for human kallikreins hK2 and hK3. Eur J Biochem. 2001;268(10):2960–8. doi:10.1046/j.1432-1327.2001.02185.x.

    PubMed  CAS  Google Scholar 

  90. Yu H, Berkel H. Prostate-specific antigen (PSA) in women. J La State Med Soc. 1999;151(4):209–13.

    PubMed  CAS  Google Scholar 

  91. Narita D, Anghel A, Motoc M. Prostate-specific antigen may serve as a pathological predictor in breast cancer. Rom J Morphol Embryol. 2008;49(2):173–80.

    PubMed  Google Scholar 

  92. Sauter ER, Daly M, Linahan K, Ehya H, Engstrom PF, Bonney G, et al. Prostate-specific antigen levels in nipple aspirate fluid correlate with breast cancer risk. Cancer Epidemiol Biomarkers Prev. 1996;5(12):967–70.

    PubMed  CAS  Google Scholar 

  93. Radowicki S, Kunicki M, Bandurska-Stankiewicz E. Prostate-specific antigen in the serum of women with benign breast disease. Eur J Obstet Gynecol Reprod Biol. 2008;138(2):212–6. doi:10.1016/j.ejogrb.2007.05.023.

    PubMed  CAS  Google Scholar 

  94. Sauter ER, Chervoneva I, Diamandis A, Khosravi JM, Litwin S, Diamandis EP. Prostate-specific antigen and insulin-like growth factor binding protein-3 in nipple aspirate fluid are associated with breast cancer. Cancer Detect Prev. 2002;26(2):149–57. doi:10.1016/S0361-090X(02)00028-4.

    PubMed  CAS  Google Scholar 

  95. Narita D, Cimpean AM, Anghel A, Raica M. Prostate-specific antigen value as a marker in breast cancer. Neoplasma. 2006;53(2):161–7.

    PubMed  CAS  Google Scholar 

  96. Yang Q, Nakamura M, Nakamura Y, Yoshimura G, Suzuma T, Umemura T, et al. Correlation of prostate-specific antigen promoter polymorphisms with clinicopathological characteristics in breast cancer. Anticancer Res. 2002;22(3):1825–8.

    PubMed  CAS  Google Scholar 

  97. Look MP, Foekens JA. Clinical relevance of the urokinase plasminogen activator system in breast cancer. APMIS. 1999;107(1):150–9.

    PubMed  CAS  Google Scholar 

  98. Descotes F, Ville G, Bobin JY, Barbier Y, Saez S. Tissue extraction procedures for investigation of urokinase plasminogen activator (uPA) and its inhibitors PAI-1 and PAI-2 in human breast carcinomas. Breast Cancer Res Treat. 1998;49(2):135–43. doi:10.1023/A:1006015529564.

    PubMed  CAS  Google Scholar 

  99. Hurd TC, Sait S, Kohga S, Winston J, Martinick M, Saxena R, et al. Plasminogen activator system localization in 60 cases of ductal carcinoma in situ. Ann Surg Oncol. 2007;14(11):3117–24. doi:10.1245/s10434-007-9529-y.

    PubMed  Google Scholar 

  100. Annecke K, Schmitt M, Euler U, Zerm M, Paepke D, Paepke S, et al. uPA and PAI-1 in breast cancer: review of their clinical utility and current validation in the prospective NNBC-3 trial. Adv Clin Chem. 2008;45:31–45. doi:10.1016/S0065-2423(07)00002-9.

    PubMed  CAS  Google Scholar 

  101. Tyndall JD, Kelso MJ, Clingan P, Ranson M. Peptides and small molecules targeting the plasminogen activation system: towards prophylactic anti-metastasis drugs for breast cancer. Recent Patents Anticancer Drug Discov 2008;3(1):1–13.

    PubMed  CAS  Google Scholar 

  102. Campbell PG, Durham SK, Suwanichkul A, Hayes JD, Powell DR. Plasminogen binds the heparin-binding domain of insulin-like growth factor-binding protein-3. Am J Physiol. 1998;275(2 Pt 1):E321–31.

    PubMed  CAS  Google Scholar 

  103. Campbell PG, Andress DL. Plasmin degradation of insulin-like growth factor-binding protein-5 (IGFBP-5): regulation by IGFBP-5-(201-218). Am J Physiol. 1997;273(5 Pt 1):E996–1004.

    PubMed  CAS  Google Scholar 

  104. Nam TJ, Busby W Jr, Clemmons DR. Insulin-like growth factor binding protein-5 binds to plasminogen activator inhibitor-I. Endocrinology. 1997;138(7):2972–8. doi:10.1210/en.138.7.2972.

    PubMed  CAS  Google Scholar 

  105. Sorrell AM, Shand JH, Tonner E, Gamberoni M, Accorsi PA, Beattie J, et al. Insulin-like growth factor binding protein-5 activates plasminogen by interaction with tissue plasminogen activator, independently of its ability to bind to plasminogen activator inhibitor-1, insulin-like growth factor-I or heparin. J Biol Chem. 2006;281:10883–9.

    PubMed  CAS  Google Scholar 

  106. Lalou C, Lassarre C, Binoux M. A proteolytic fragment of insulin-like growth factor (IGF) binding protein-3 that fails to bind IGFs inhibits the mitogenic effects of IGF-I and insulin. Endocrinology. 1996;137(8):3206–12. doi:10.1210/en.137.8.3206.

    PubMed  CAS  Google Scholar 

  107. Rochefort H, Capony F, Garcia M. Cathepsin D: a protease involved in breast cancer metastasis. Cancer Metastasis Rev. 1990;9(4):321–31. doi:10.1007/BF00049522.

    PubMed  CAS  Google Scholar 

  108. De Leon DD, Issa N, Nainani S, Asmerom Y. Reversal of cathepsin D routing modulation in MCF-7 breast cancer cells expressing antisense insulin-like growth factor II (IGF-II). Horm Metab Res. 1999;31(2–3):142–7. doi:10.1055/s-2007-978712.

    PubMed  Google Scholar 

  109. Mathieu M, Rochefort H, Barenton B, Prebois C, Vignon F. Interactions of cathepsin-D and insulin-like growth factor-II (IGF-II) on the IGF-II/mannose-6-phosphate receptor in human breast cancer cells and possible consequences on mitogenic activity of IGF-II. Mol Endocrinol. 1990;4(9):1327–35.

    PubMed  CAS  Google Scholar 

  110. Cappelletti V, Fioravanti L, Miodini P, Di Fronzo G. Modulation of cathepsin-D and pS2 protein levels in human breast cancer cell lines. Tumour Biol. 1996;17(5):290–8.

    PubMed  CAS  Google Scholar 

  111. Conover CA. Insulin-like growth factor binding protein proteolysis in bone cell models. Prog Growth Factor Res. 1995;6(2–4):301–9. doi:10.1016/0955-2235(95)00032-1.

    PubMed  CAS  Google Scholar 

  112. Coverley JA, Baxter RC. Phosphorylation of insulin-like growth factor binding proteins. Mol Cell Endocrinol. 1997;128(1–2):1–5. doi:10.1016/S0303-7207(97)04032-X.

    PubMed  CAS  Google Scholar 

  113. Jones JI, D’Ercole AJ, Camacho-Hubner C, Clemmons DR. Phosphorylation of insulin-like growth factor (IGF)-binding protein 1 in cell culture and in vivo: effects on affinity for IGF-I. Proc Natl Acad Sci U S A. 1991;88(17):7481–5. doi:10.1073/pnas.88.17.7481.

    PubMed  CAS  Google Scholar 

  114. Coverley JA, Martin JL, Baxter RC. The effect of phosphorylation by casein kinase 2 on the activity of insulin-like growth factor-binding protein-3. Endocrinology. 2000;141(2):564–70. doi:10.1210/en.141.2.564.

    PubMed  CAS  Google Scholar 

  115. Martin JL, Coverley JA, Pattison ST, Baxter RC. Insulin-like growth factor-binding protein-3 production by MCF-7 breast cancer cells: stimulation by retinoic acid and cyclic adenosine monophosphate and differential effects of estradiol. Endocrinology. 1995;136(3):1219–26. doi:10.1210/en.136.3.1219.

    PubMed  CAS  Google Scholar 

  116. Silha JV, Sheppard PC, Mishra S, Gui Y, Schwartz J, Dodd JG, et al. Insulin-like growth factor binding protein-3 attenuates prostate tumor growth by IGF-dependent and IGF-independent mechanisms. Endocrinology. 2006;147:2112–21.

    PubMed  CAS  Google Scholar 

  117. Schedlich LJ, Nilsen T, John AP, Jans DA, Baxter RC. Phosphorylation of insulin-like growth factor binding protein-3 by deoxyribonucleic acid-dependent protein kinase reduces ligand binding and enhances nuclear accumulation. Endocrinology. 2003;144(5):1984–93. doi:10.1210/en.2002-220798.

    PubMed  CAS  Google Scholar 

  118. Conover CA. Glycosylation of insulin-like growth factor binding protein-3 (IGFBP-3) is not required for potentiation of IGF-I action: evidence for processing of cell-bound IGFBP-3. Endocrinology. 1991;129(6):3259–68.

    PubMed  CAS  Google Scholar 

  119. Jones JI, Gockerman A, Busby WH Jr, Camacho-Hubner C, Clemmons DR. Extracellular matrix contains insulin-like growth factor binding protein-5: potentiation of the effects of IGF-I. J Cell Biol. 1993;121(3):679–87. doi:10.1083/jcb.121.3.679.

    PubMed  CAS  Google Scholar 

  120. Clemmons DR. IGF binding proteins: regulation of cellular actions. Growth Regul. 1992;2(2):80–7.

    PubMed  CAS  Google Scholar 

  121. Rechler MM. Insulin-like growth factor binding proteins. Vitam Horm. 1993;47:1–114. doi:10.1016/S0083-6729(08)60444-6.

    PubMed  CAS  Google Scholar 

  122. Bach LA, Thotakura NR, Rechler MM. Human insulin-like growth factor binding protein-6 is O-glycosylated. Growth Regul. 1993;3(1):59–62.

    PubMed  CAS  Google Scholar 

  123. Firth SM, Baxter RC. The role of glycosylation in the action of IGFBP-3. Prog Growth Factor Res. 1995;6(2–4):223–9. doi:10.1016/0955-2235(95)00009-7.

    PubMed  CAS  Google Scholar 

  124. Perks CM, McCaig C, Clarke JB, Clemmons DR, Holly JM. A non-IGF binding mutant of IGFBP-3 modulates cell function in breast epithelial cells. Biochem Biophys Res Commun. 2002;294(5):988–94. doi:10.1016/S0006-291X(02)00569-7.

    PubMed  CAS  Google Scholar 

  125. Firth SM, Baxter RC. Characterisation of recombinant glycosylation variants of insulin-like growth factor binding protein-3. J Endocrinol. 1999;160(3):379–87. doi:10.1677/joe.0.1600379.

    PubMed  CAS  Google Scholar 

  126. Jones JI, Clemmons DR. Insulin-like growth factors and their binding proteins: biological actions. Endocr Rev. 1995;16(1):3–34. doi:10.1210/er.16.1.3.

    PubMed  CAS  Google Scholar 

  127. Blum WF, Jenne EW, Reppin F, Kietzmann K, Ranke MB, Bierich JR. Insulin-like growth factor I (IGF-I)-binding protein complex is a better mitogen than free IGF-I. Endocrinology. 1989;125(2):766–72.

    Article  PubMed  CAS  Google Scholar 

  128. Nickerson T, Huynh H, Pollak M. Insulin-like growth factor binding protein-3 induces apoptosis in MCF7 breast cancer cells. Biochem Biophys Res Commun. 1997;237(3):690–3. doi:10.1006/bbrc.1997.7089.

    PubMed  CAS  Google Scholar 

  129. Jerome L, Alami N, Belanger S, Page V, Yu Q, Paterson J, et al. Recombinant human insulin-like growth factor binding protein 3 inhibits growth of human epidermal growth factor receptor-2-overexpressing breast tumors and potentiates herceptin activity in vivo. Cancer Res. 2006;66(14):7245–52. doi:10.1158/0008-5472.CAN-05-3555.

    PubMed  CAS  Google Scholar 

  130. Firth SM, Fanayan S, Benn D, Baxter RC. Development of resistance to insulin-like growth factor binding protein-3 in transfected T47D breast cancer cells. Biochem Biophys Res Commun. 1998;246(2):325–9. doi:10.1006/bbrc.1998.8615.

    PubMed  CAS  Google Scholar 

  131. Figueroa JA, Sharma J, Jackson JG, McDermott MJ, Hilsenbeck SG, Yee D. Recombinant insulin-like growth factor binding protein-1 inhibits IGF-I, serum, and estrogen-dependent growth of MCF-7 human breast cancer cells. J Cell Physiol. 1993;157(2):229–36. doi:10.1002/jcp.1041570204.

    PubMed  CAS  Google Scholar 

  132. McGuire WL Jr, Jackson JG, Figueroa JA, Shimasaki S, Powell DR, Yee D. 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. 1992;84(17):1336–41. doi:10.1093/jnci/84.17.1336.

    PubMed  CAS  Google Scholar 

  133. Yee D, Jackson JG, Kozelsky TW, Figueroa JA. Insulin-like growth factor binding protein 1 expression inhibits insulin-like growth factor I action in MCF-7 breast cancer cells. Cell Growth Differ. 1994;5(1):73–7.

    PubMed  CAS  Google Scholar 

  134. Butt AJ, Firth SM, King MA, Baxter RC. Insulin-like growth factor-binding protein-3 modulates expression of Bax and Bcl-2 and potentiates p53-independent radiation-induced apoptosis in human breast cancer cells. J Biol Chem. 2000;275(50):39174–81. doi:10.1074/jbc.M908888199.

    PubMed  CAS  Google Scholar 

  135. Collard TJ, Guy M, Butt AJ, Perks CM, Holly JM, Paraskeva C, et al. Transcriptional upregulation of the insulin-like growth factor binding protein IGFBP-3 by sodium butyrate increases IGF-independent apoptosis in human colonic adenoma-derived epithelial cells. Carcinogenesis. 2003;24(3):393–401. doi:10.1093/carcin/24.3.393.

    PubMed  CAS  Google Scholar 

  136. Gill ZP, Perks CM, Newcomb PV, Holly JM. Insulin-like growth factor-binding protein (IGFBP-3) predisposes breast cancer cells to programmed cell death in a non-IGF-dependent manner. J Biol Chem. 1997;272(41):25602–7. doi:10.1074/jbc.272.41.25602.

    PubMed  CAS  Google Scholar 

  137. Fowler CA, Perks CM, Newcomb PV, Savage PB, Farndon JR, Holly JM. Insulin-like growth factor binding protein-3 (IGFBP-3) potentiates paclitaxel-induced apoptosis in human breast cancer cells. Int J Cancer. 2000;88(3):448–53. doi:10.1002/1097-0215(20001101)88:3<448::AID-IJC18>3.0.CO;2-V.

    PubMed  CAS  Google Scholar 

  138. Perks CM, McCaig C, Holly JM. Differential insulin-like growth factor (IGF)-independent interactions of IGF binding protein-3 and IGF binding protein-5 on apoptosis in human breast cancer cells. Involvement of the mitochondria. J Cell Biochem. 2000;80(2):248–58. doi:10.1002/1097-4644(20010201)80:2<248::AID-JCB140>3.0.CO;2-4.

    PubMed  CAS  Google Scholar 

  139. Buckbinder L, Talbott R, Velasco-Miguel S, Takenaka I, Faha B, Seizinger BR, et al. Induction of the growth inhibitor IGF-binding protein 3 by p53. Nature. 1995;377(6550):646–9. doi:10.1038/377646a0.

    PubMed  CAS  Google Scholar 

  140. Hollowood AD, Lai T, Perks CM, Newcomb PV, Alderson D, Holly JM. IGFBP-3 prolongs the p53 response and enhances apoptosis following UV irradiation. Int J Cancer. 2000;88(3):336–41. doi:10.1002/1097-0215(20001101)88:3<336::AID-IJC3>3.0.CO;2-A.

    PubMed  CAS  Google Scholar 

  141. Williams AC, Collard TJ, Perks CM, Newcomb P, Moorghen M, Holly JM, et al. Increased p53-dependent apoptosis by the insulin-like growth factor binding protein IGFBP-3 in human colonic adenoma-derived cells. Cancer Res. 2000;60(1):22–7.

    PubMed  CAS  Google Scholar 

  142. Perks CM, Bowen S, Gill ZP, Newcomb PV, Holly JM. Differential IGF-independent effects of insulin-like growth factor binding proteins (1–6) on apoptosis of breast epithelial cells. J Cell Biochem. 1999;75(4):652–64. doi:10.1002/(SICI)1097-4644(19991215)75:4<652::AID-JCB11>3.0.CO;2-0.

    PubMed  CAS  Google Scholar 

  143. Butt AJ, Dickson KA, Jambazov S, Baxter RC. 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. 2005;146(7):3113–22. doi:10.1210/en.2004-1408.

    PubMed  CAS  Google Scholar 

  144. Perks CM, McCaig C, Clarke JB, Clemmons DR, Holly JM. Effects of a non-IGF binding mutant of IGFBP-5 on cell death in human breast cancer cells. Biochem Biophys Res Commun. 2002;294(5):995–1000. doi:10.1016/S0006-291X(02)00570-3.

    PubMed  CAS  Google Scholar 

  145. Martin JL, Jambazov S. Insulin-like growth factor binding protein-3 in extracellular matrix stimulates adhesion of breast epithelial cells and activation of p44/42 mitogen-activated protein kinase. Endocrinology. 2006;147(9):4400–9. doi:10.1210/en.2006-0094.

    PubMed  CAS  Google Scholar 

  146. Perks CM, Newcomb PV, Norman MR, Holly JM. Effect of insulin-like growth factor binding protein-1 on integrin signalling and the induction of apoptosis in human breast cancer cells. J Mol Endocrinol. 1999;22(2):141–50. doi:10.1677/jme.0.0220141.

    PubMed  CAS  Google Scholar 

  147. Schutt B, Langkamp M, Ranke M, Elmlinger M. Intracellular signalling of insulin-like growth factor binding protein-2. Growth Horm IGF Res. 2000;10:A30. Abstract 35.

    Google Scholar 

  148. Irving JA, Lala PK. Functional role of cell surface integrins on human trophoblast cell migration: regulation by TGF-beta, IGF-II, and IGFBP-1. Exp Cell Res. 1995;217(2):419–27. doi:10.1006/excr.1995.1105.

    PubMed  CAS  Google Scholar 

  149. Jones JI, Doerr ME, Clemmons DR. Cell migration: interactions among integrins, IGFs and IGFBPs. Prog Growth Factor Res. 1995;6(2–4):319–27. doi:10.1016/0955-2235(95)00015-1.

    PubMed  CAS  Google Scholar 

  150. Clemmons DR, Busby WH, Arai T, Nam TJ, Clarke JB, Jones JI, et al. Role of insulin-like growth factor binding proteins in the control of IGF actions. Prog Growth Factor Res. 1995;6(2–4):357–66. doi:10.1016/0955-2235(95)00013-5.

    PubMed  CAS  Google Scholar 

  151. Jones JI, Gockerman A, Busby WH Jr, Wright G, Clemmons DR. Insulin-like growth factor binding protein 1 stimulates cell migration and binds to the alpha 5 beta 1 integrin by means of its Arg-Gly-Asp sequence. Proc Natl Acad Sci U S A. 1993;90(22):10553–7. doi:10.1073/pnas.90.22.10553.

    PubMed  CAS  Google Scholar 

  152. Kiepe D, Van Der Pas A, Ciarmatori S, Standker L, Schutt B, Hoeflich A, et al. Defined carboxy-terminal fragments of insulin-like growth factor (IGF) binding protein-2 exert similar mitogenic activity on cultured rat growth plate chondrocytes as IGF-I. Endocrinology. 2008;149(10):4901–11. doi:10.1210/en.2007-1395.

    PubMed  CAS  Google Scholar 

  153. Andress DL. Insulin-like growth factor-binding protein-5 (IGFBP-5) stimulates phosphorylation of the IGFBP-5 receptor. Am J Physiol. 1998;274(4 Pt 1):E744–50.

    PubMed  CAS  Google Scholar 

  154. Oh Y, Muller HL, Pham H, Rosenfeld RG. Demonstration of receptors for insulin-like growth factor binding protein-3 on Hs578T human breast cancer cells. J Biol Chem. 1993;268(35):26045–8.

    PubMed  CAS  Google Scholar 

  155. Leal SM, Liu Q, Huang SS, Huang JS. The type V transforming growth factor beta receptor is the putative insulin-like growth factor-binding protein 3 receptor. J Biol Chem. 1997;272(33):20572–6. doi:10.1074/jbc.272.33.20572.

    PubMed  CAS  Google Scholar 

  156. Burrows C, Holly JM, Laurence NJ, Vernon EG, Carter JV, Clark MA, et al. Insulin-like growth factor binding protein 3 has opposing actions on malignant and nonmalignant breast epithelial cells that are each reversible and dependent upon cholesterol-stabilized integrin receptor complexes. Endocrinology. 2006;147(7):3484–500. doi:10.1210/en.2006-0005.

    PubMed  CAS  Google Scholar 

  157. Gui Y, Murphy LJ. Insulin-like growth factor (IGF)-binding protein-3 (IGFBP-3) binds to fibronectin (FN): demonstration of IGF-I/IGFBP-3/fn ternary complexes in human plasma. J Clin Endocrinol Metab. 2001;86(5):2104–10. doi:10.1210/jc.86.5.2104.

    PubMed  CAS  Google Scholar 

  158. Shi Z, Xu W, Loechel F, Wewer UM, Murphy LJ. ADAM 12, a disintegrin metalloprotease, interacts with insulin-like growth factor-binding protein-3. J Biol Chem. 2000;275(24):18574–80. doi:10.1074/jbc.M002172200.

    PubMed  CAS  Google Scholar 

  159. Nam TJ, Busby WH Jr, Rees C, Clemmons DR. Thrombospondin and osteopontin bind to insulin-like growth factor (IGF)-binding protein-5 leading to an alteration in IGF-I-stimulated cell growth. Endocrinology. 2000;141(3):1100–6. doi:10.1210/en.141.3.1100.

    PubMed  CAS  Google Scholar 

  160. Singh B, Charkowicz D, Mascarenhas D. Insulin-like growth factor-independent effects mediated by a C-terminal metal-binding domain of insulin-like growth factor binding protein-3. J Biol Chem. 2004;279(1):477–87. doi:10.1074/jbc.M307322200.

    PubMed  CAS  Google Scholar 

  161. Lee HY, Moon H, Chun KH, Chang YS, Hassan K, Ji L, et al. Effects of insulin-like growth factor binding protein-3 and farnesyltransferase inhibitor SCH66336 on Akt expression and apoptosis in non-small-cell lung cancer cells. J Natl Cancer Inst. 2004;96(20):1536–48.

    Article  PubMed  CAS  Google Scholar 

  162. McCaig C, Perks C, Holly J. MAP Kinase inhibitor blocks IGF-independent effect of IGFBP-3 on breast epithelial cell survival and cell attachment. Proceedings of the Endocrine Society’s 83rd Annual Meeting 2001;P2:268.

    Google Scholar 

  163. McCaig C, Perks CM, Holly JM. Signalling pathways involved in the direct effects of IGFBP-5 on breast epithelial cell attachment and survival. J Cell Biochem. 2002;84(4):784–94. doi:10.1002/jcb.10093.

    PubMed  Google Scholar 

  164. Firth SM, Ganeshprasad U, Baxter RC. Structural determinants of ligand and cell surface binding of insulin-like growth factor-binding protein-3. J Biol Chem. 1998;273(5):2631–8. doi:10.1074/jbc.273.5.2631.

    PubMed  CAS  Google Scholar 

  165. Yamanaka Y, Fowlkes JL, Wilson EM, Rosenfeld RG, Oh Y. Characterization of insulin-like growth factor binding protein-3 (IGFBP-3) binding to human breast cancer cells: kinetics of IGFBP-3 binding and identification of receptor binding domain on the IGFBP-3 molecule. Endocrinology. 1999;140(3):1319–28. doi:10.1210/en.140.3.1319.

    PubMed  CAS  Google Scholar 

  166. Hollowood AD, Stewart CE, Perks CM, Pell JM, Lai T, Alderson D, et al. Evidence implicating a mid-region sequence of IGFBP-3 in its specific IGF-independent actions. J Cell Biochem. 2002;86(3):583–9. doi:10.1002/jcb.10223.

    PubMed  CAS  Google Scholar 

  167. Schedlich LJ, Young TF, Firth SM, Baxter RC. 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. 1998;273(29):18347–52. doi:10.1074/jbc.273.29.18347.

    PubMed  CAS  Google Scholar 

  168. Liu B, Lee HY, Weinzimer SA, Powell DR, Clifford JL, Kurie JM, et al. Direct functional interactions between insulin-like growth factor-binding protein-3 and retinoid X receptor-alpha regulate transcriptional signaling and apoptosis. J Biol Chem. 2000;275(43):33607–13. doi:10.1074/jbc.M002547200.

    PubMed  CAS  Google Scholar 

  169. Lee KW, Ma L, Yan X, Liu B, Zhang XK, Cohen P. Rapid apoptosis induction by IGFBP-3 involves an insulin-like growth factor-independent nucleomitochondrial translocation of RXRalpha/Nur77. J Biol Chem. 2005;280(17):16942–8. doi:10.1074/jbc.M412757200.

    PubMed  CAS  Google Scholar 

  170. Zappala G, Elbi C, Edwards J, Gorenstein J, Rechler MM, Bhattacharyya N. Induction of apoptosis in human prostate cancer cells by insulin-like growth factor binding protein-3 does not require binding to retinoid X receptor-alpha. Endocrinology. 2008;149(4):1802–12. doi:10.1210/en.2007-1315.

    PubMed  CAS  Google Scholar 

  171. Bhattacharyya N, Pechhold K, Shahjee H, Zappala G, Elbi C, Raaka B, et al. Nonsecreted insulin-like growth factor binding protein-3 (IGFBP-3) can induce apoptosis in human prostate cancer cells by IGF-independent mechanisms without being concentrated in the nucleus. J Biol Chem. 2006;281(34):24588–601. doi:10.1074/jbc.M509463200.

    PubMed  CAS  Google Scholar 

  172. Jurgeit A, Berlato C, Obrist P, Ploner C, Massoner P, Schmolzer J, et al. Insulin-like growth factor-binding protein-5 enters vesicular structures but not the nucleus. Traffic. 2007;8(12):1815–28. doi:10.1111/j.1600-0854.2007.00655.x.

    PubMed  CAS  Google Scholar 

  173. Fanayan S, Firth SM, Butt AJ, Baxter RC. Growth inhibition by insulin-like growth factor-binding protein-3 in T47D breast cancer cells requires transforming growth factor-beta (TGF-beta) and the type II TGF-beta receptor. J Biol Chem. 2000;275(50):39146–51. doi:10.1074/jbc.M006964200.

    PubMed  CAS  Google Scholar 

  174. Fu P, Thompson JA, Bach LA. Promotion of cancer cell migration: an insulin-like growth factor (IGF)-independent action of IGF-binding protein-6. J Biol Chem. 2007;282(31):22298–306. doi:10.1074/jbc.M703066200.

    PubMed  CAS  Google Scholar 

  175. Yu Q, Banerjee K, Paterson J, Alami N, Shiry L, Leyland-Jones B. Insulin-like growth factor binding protein-3: single-agent and synergistic effects with chemotherapeutic drugs on solid tumor models. In: Proceedings of the AACR, Abstract 755, Washington DC; 2003. p. 172.

  176. Ioachim E, Charchanti A, Briasoulis E, Karavasilis V, Tsanou H, Arvanitis DL, et al. Immunohistochemical expression of extracellular matrix components tenascin, fibronectin, collagen type IV and laminin in breast cancer: their prognostic value and role in tumour invasion and progression. Eur J Cancer. 2002;38(18):2362–70. doi:10.1016/S0959-8049(02)00210-1.

    PubMed  CAS  Google Scholar 

  177. Zhou J, Wulfkuhle J, Zhang H, Gu P, Yang Y, Deng J, et al. Activation of the PTEN/mTOR/STAT3 pathway in breast cancer stem-like cells is required for viability and maintenance. Proc Natl Acad Sci U S A. 2007;104(41):16158–63. doi:10.1073/pnas.0702596104.

    PubMed  CAS  Google Scholar 

  178. Clark AS, West K, Streicher S, Dennis PA. Constitutive and inducible Akt activity promotes resistance to chemotherapy, trastuzumab, or tamoxifen in breast cancer cells. Mol Cancer Ther. 2002;1(9):707–17.

    PubMed  CAS  Google Scholar 

  179. Kalli KR, Krco CJ, Hartmann LC, Goodman K, Maurer MJ, Yu C, et al. An HLA-DR-degenerate epitope pool detects insulin-like growth factor binding protein 2-specific immunity in patients with cancer. Cancer Res. 2008;68(12):4893–901. doi:10.1158/0008-5472.CAN-07-6726.

    PubMed  CAS  Google Scholar 

  180. Zhang X, Yee D. Insulin-like growth factor binding protein-1 (IGFBP-1) inhibits breast cancer cell motility. Cancer Res. 2002;62(15):4369–75.

    PubMed  CAS  Google Scholar 

  181. Subramanian A, Sharma AK, Banerjee D, Jiang WG, Mokbel K. Evidence for a tumour suppressive function of IGF1-binding proteins in human breast cancer. Anticancer Res. 2007;27(5B):3513–8.

    PubMed  CAS  Google Scholar 

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Acknowledgements

We thank The Breast Cancer Campaign for supporting our work.

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  1. Department of Clinical Sciences North Bristol, IGFs and Metabolic Endocrinology Group, University of Bristol, Southmead Hospital, The Medical School Unit, Bristol, BS10 5NB, UK

    Claire M. Perks & Jeff M. P. Holly

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  1. Claire M. Perks
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  2. Jeff M. P. Holly
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Correspondence to Claire M. Perks.

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Perks, C.M., Holly, J.M.P. IGF Binding Proteins (IGFBPs) and Regulation of Breast Cancer Biology. J Mammary Gland Biol Neoplasia 13, 455–469 (2008). https://doi.org/10.1007/s10911-008-9106-4

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