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Insulin-like growth factor receptor polymorphism defines clinical outcome in estrogen receptor-positive breast cancer patients treated with tamoxifen

Abstract

Compelling evidence points to a key role for insulin-like growth factor 1 (IGF1) signaling in breast cancer development and progression. In addition, IGF1 receptor (IGF1R) expression has been correlated and functionally linked with estrogen receptor (ER) signaling. Recent translational studies support a cross talk between IGF1R and ERĪ± at different levels and data suggest enhanced IGF1R signaling as a causative mechanism of tamoxifen (TAM) resistance. We tested whether functional germline variations in the IGF pathway are associated with clinical outcome in ER-positive primary invasive breast cancer patients, who were treated with surgery and adjuvant TAM. Tissue samples of 222 patients with ER+ primary invasive breast cancer, who had undergone surgery at Charing Cross Hospital, London, UK between 1981 and 2003, were analyzed. Genomic DNA was extracted from formalin-fixed, paraffin-embedded tissue samples and six functional IGF1 pathway polymorphisms were analyzed using direct DNA sequencing and PCR-restriction fragment length polymorphism. In multivariable analysis, patients with primary invasive breast cancer carrying IGF1R_rs2016347 G allele had a significantly increased risk of early tumor progression (hazard ratio (HR) 2.01; adjusted P=0.004) and death (HR 1.84; adjusted P=0.023) compared with patients carrying G/T or T/T, independent of established clinicopathological determinants. This association remained significant after adjusting for multiple testing. In addition, we were able to demonstrate that IRS1_rs1801123 and IGFBP3_rs2854744 were significantly associated with lymph node involvement and tumor size, respectively. We provide the first evidence for IGF1R_rs2016347 as an independent prognostic marker for ER+ breast cancer patients treated with TAM and support a rational for combined treatment strategies.

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References

  1. Siegel R, DeSantis C, Virgo K, Stein K, Mariotto A, Smith T et al. Cancer treatment and survivorship statistics, 2012. Cancer J Clin 2012; 62: 220ā€“241.

    ArticleĀ  Google ScholarĀ 

  2. Wickerham L . Tamoxifenā€”an update on current data and where it can now be used. Br Cancer Res Treat 2002; 75 (Suppl 1): S7ā€“12, discussion S33-15.

    ArticleĀ  CASĀ  Google ScholarĀ 

  3. Hammond ME, Hayes DF, Dowsett M, Allred DC, Hagerty KL, Badve S et al. American Society of Clinical Oncology/College Of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. J Clin Oncol 2010; 28: 2784ā€“2795.

    ArticleĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  4. Jiang J, Sarwar N, Peston D, Kulinskaya E, Shousha S, Coombes RC et al. Phosphorylation of estrogen receptor-alpha at Ser167 is indicative of longer disease-free and overall survival in breast cancer patients. Clin Cancer Res 2007; 13: 5769ā€“5776.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  5. Ali S, Coombes RC . Endocrine-responsive breast cancer and strategies for combating resistance. Nat Rev Cancer 2002; 2: 101ā€“112.

    ArticleĀ  PubMedĀ  Google ScholarĀ 

  6. Cordera F, Jordan VC . Steroid receptors and their role in the biology and control of breast cancer growth. Semin Oncol 2006; 33: 631ā€“641.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  7. Herynk MH, Fuqua SA . Estrogen receptors in resistance to hormone therapy. Adv Exp Med Biol 2007; 608: 130ā€“143.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  8. Musgrove EA, Sutherland RL . Biological determinants of endocrine resistance in breast cancer. Nat Rev Cancer 2009; 9: 631ā€“643.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  9. Forbes JF, Cuzick J, Buzdar A, Howell A, Tobias JS, Baum M . Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 100-month analysis of the ATAC trial. Lancet Oncol 2008; 9: 45ā€“53.

    ArticleĀ  PubMedĀ  Google ScholarĀ 

  10. Ellis MJ, Tao Y, Young O, White S, Proia AD, Murray J et al. Estrogen-independent proliferation is present in estrogen-receptor HER2-positive primary breast cancer after neoadjuvant letrozole. J Clin Oncol 2006; 24: 3019ā€“3025.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  11. Jordan VC, Oā€™Malley BW . Selective estrogen-receptor modulators and antihormonal resistance in breast cancer. J Clin Oncol 2007; 25: 5815ā€“5824.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  12. Tokunaga E, Kimura Y, Mashino K, Oki E, Kataoka A, Ohno S et al. Activation of PI3K/Akt signaling and hormone resistance in breast cancer. Breast Cancer 2006; 13: 137ā€“144.

    ArticleĀ  PubMedĀ  Google ScholarĀ 

  13. Jeng MH, Yue W, Eischeid A, Wang JP, Santen RJ . Role of MAP kinase in the enhanced cell proliferation of long term estrogen deprived human breast cancer cells. Breast Cancer Res Treat 2000; 62: 167ā€“175.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  14. Riggins RB, Schrecengost RS, Guerrero MS, Bouton AH . Pathways to tamoxifen resistnce. Cancer Lett 2007; 256: 1ā€“24.

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  15. Frogne T, Benjaminsen RV, Sonne-Hansen K, Sorensen BS, Nexo E, Laenkholm AV et al. Activation of ErbB3, EGFR and Erk is essential for growth of human breast cancer cell lines with acquired resistance to fulvestrant. Breast Cancer Res Treat 2009; 114: 263ā€“275.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  16. Stebbing J, Filipovic A, Ellis IO, Green AR, Dā€™Silva TR, Lenz HJ et al. LMTK3 expression in breast cancer: association with tumor phenotype and clinical outcome. Breast Cancer Res Treat 2012; 132: 537ā€“544.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  17. Giamas G, Filipovic A, Jacob J, Messier W, Zhang H, Yang D et al. Kinome screening for regulators of the estrogen receptor identifies LMTK3 as a new therapeutic target in breast cancer. Nat Med 2011; 17: 715ā€“719.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  18. Stebbing J, Filipovic A, Lit LC, Blighe K, Grothey A, Xu Y et al. LMTK3 is implicated in endocrine resistance via multiple signaling pathways. Oncogene, advance online publication, 6 August 2012; doi:10.1038/onc.2012.343 (e-pub ahead of print).

    ArticleĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  19. Fox EM, Miller TW, Balko JM, Kuba MG, Sanchez V, Smith RA et al. A kinome-wide screen identifies the insulin/IGF-I receptor pathway as a mechanism of escape from hormone dependence in breast cancer. Cancer Res 2011; 71: 6773ā€“6784.

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  20. Periyasamy-Thandavan S, Takhar S, Singer A, Dohn MR, Jackson WH, Welborn AE et al. Insulin-like growth factor 1 attenuates antiestrogen- and antiprogestin-induced apoptosis in ER+ breast cancer cells by MEK1 regulation of the BH3-only pro-apoptotic protein Bim. Breast Cancer Res 2012; 14: R52.

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  21. Zhang Y, Moerkens M, Ramaiahgari S, de Bont H, Price L, Meerman J et al. Elevated insulin-like growth factor 1 receptor signaling induces antiestrogen resistance through the MAPK/ERK and PI3K/Akt signaling routes. Breast Cancer Res 2011; 13: R52.

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  22. Massarweh S, Osborne CK, Creighton CJ, Qin L, Tsimelzon A, Huang S et al. Tamoxifen resistance in breast tumors is driven by growth factor receptor signaling with repression of classic estrogen receptor genomic function. Cancer Res 2008; 68: 826ā€“833.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  23. Hicks C, Kumar R, Pannuti A, Miele L . Integrative analysis of response to tamoxifen treatment in ER-positive breast cancer using GWAS information and transcription profiling. Breast Cancer: basic and clinical research 2012; 6: 47ā€“66.

    Google ScholarĀ 

  24. Winder T, Zhang W, Yang D, Ning Y, Bohanes P, Gerger A et al. Germline polymorphisms in genes involved in the IGF1 pathway predict efficacy of cetuximab in wild-type KRAS mCRC patients. Clin Cancer Res 2010; 16: 5591ā€“5602.

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  25. Sarwar N, Kim JS, Jiang J, Peston D, Sinnett HD, Madden P et al. Phosphorylation of ERalpha at serine 118 in primary breast cancer and in tamoxifen-resistant tumours is indicative of a complex role for ERalpha phosphorylation in breast cancer progression. Endocr Relat Cancer 2006; 13: 851ā€“861.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  26. Lee PH, Shatkay H . F-SNP: computationally predicted functional SNPs for disease association studies. Nucleic Acids Res 2008; 36, Database issue D820ā€“D824.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  27. Lee PH, Shatkay H . An integrative scoring system for ranking SNPs by their potential deleterious effects. Bioinformatics 2009; 25: 1048ā€“1055.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  28. Conneely KN, Boehnke M . So many correlated tests, so little time! Rapid adjustment of P values for multiple correlated tests. Am J Hum Genet 2007; 81: 1158ā€“1168.

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  29. McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM et al. Reporting recommendations for tumor marker prognostic studies (REMARK). J Natl Cancer Inst 2005; 97: 1180ā€“1184.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  30. Samani AA, Yakar S, LeRoith D, Brodt P . The role of the IGF system in cancer growth and metastasis: overview and recent insights. Endocrine Rev 2007; 28: 20ā€“47.

    ArticleĀ  CASĀ  Google ScholarĀ 

  31. Belfiore A, Frasca F . IGF and insulin receptor signaling in breast cancer. J Mammary Gland Biol Neoplasia 2008; 13: 381ā€“406.

    ArticleĀ  PubMedĀ  Google ScholarĀ 

  32. Tanno S, Tanno S, Mitsuuchi Y, Altomare DA, Xiao GH, Testa JR . AKT activation up-regulates insulin-like growth factor I receptor expression and promotes invasiveness of human pancreatic cancer cells. Cancer Res 2001; 61: 589ā€“593.

    CASĀ  PubMedĀ  Google ScholarĀ 

  33. Key TJ, Appleby PN, Reeves GK, Roddam AW . Insulin-like growth factor 1 (IGF1), IGF binding protein 3 (IGFBP3), and breast cancer risk: pooled individual data analysis of 17 prospective studies. Lancet Oncol 2010; 11: 530ā€“542.

    ArticleĀ  PubMedĀ  Google ScholarĀ 

  34. Creighton CJ, Casa A, Lazard Z, Huang S, Tsimelzon A, Hilsenbeck SG et al. Insulin-like growth factor-I activates gene transcription programs strongly associated with poor breast cancer prognosis. J Clin Oncol 2008; 26: 4078ā€“4085.

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  35. Zhang M, Hu Z, Huang J, Shu Y, Dai J, Jin G et al. A 3ā€²-untranslated region polymorphism in IGF1 predicts survival of non-small cell lung cancer in a Chinese population. Clin Cancer Res 2010; 16: 1236ā€“1244.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  36. Tsuchiya N, Wang L, Suzuki H, Segawa T, Fukuda H, Narita S et al. Impact of IGF-I and CYP19 gene polymorphisms on the survival of patients with metastatic prostate cancer. J Clin Oncol 2006; 24: 1982ā€“1989.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  37. Lonn S, Rothman N, Shapiro WR, Fine HA, Selker RG, Black PM et al. Genetic variation in insulin-like growth factors and brain tumor risk. Neuro Oncol 2008; 10: 553ā€“559.

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  38. Levin ER . Membrane oestrogen receptor alpha signalling to cell functions. J Physiol 2009; 587 (Pt 21): 5019ā€“5023.

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  39. Fagan DH, Yee D . Crosstalk between IGF1R and estrogen receptor signaling in breast cancer. J Mammary Gland Biol Neoplasia 2008; 13: 423ā€“429.

    ArticleĀ  PubMedĀ  Google ScholarĀ 

  40. Klotz DM, Hewitt SC, Ciana P, Raviscioni M, Lindzey JK, Foley J et al. Requirement of estrogen receptor-alpha in insulin-like growth factor-1 (IGF-1)-induced uterine responses and in vivo evidence for IGF-1/estrogen receptor cross-talk. J Biol Chem 2002; 277: 8531ā€“8537.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  41. Baselga J, Campone M, Piccart M, Burris HA, Rugo HS, Sahmoud T et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. New Engl J Med 2012; 366: 520ā€“529.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  42. Bachelot T, Bourgier C, Cropet C, Ray-Coquard I, Ferrero JM, Freyer G et al. Randomized phase II trial of everolimus in combination with tamoxifen in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer with prior exposure to aromatase inhibitors: a GINECO study. J Clin Oncol 2012; 30: 2718ā€“2724.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  43. Oā€™Reilly KE, Rojo F, She QB, Solit D, Mills GB, Smith D et al. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res 2006; 66: 1500ā€“1508.

    ArticleĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  44. Di Cosimo S, Bendell JC, Cervantes-Ruiperez A, Roda D, Prudkin L, Stein MN et al. A phase I study of the oral mTOR inhibitor ridaforolimus (RIDA) in combination with the IGF-1R antibody dalotozumab (DALO) in patients (pts) with advanced solid tumors. J Clin Oncol 28: 15s (suppl, abstract 3008) 2010.

    ArticleĀ  Google ScholarĀ 

  45. Naing A, LoRusso P, Gupta S, Benjamin RS, Rohren E, Chen HX et al. Dual inhibition of IGFR and mTOR pathways. J Clin Oncol 28: 15s (suppl, abstract 3007) 2010.

    ArticleĀ  Google ScholarĀ 

  46. Feik E, Baierl A, Hieger B, Fuhrlinger G, Pentz A, Stattner S et al. Association of IGF1 and IGFBP3 polymorphisms with colorectal polyps and colorectal cancer risk. Cancer Causes Control 21: 91ā€“97.

    ArticleĀ  Google ScholarĀ 

  47. 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: 1ā€“10.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  48. Patel AV, Cheng I, Canzian F, Le Marchand L, Thun MJ, Berg CD et al. IGF-1, IGFBP-1, and IGFBP-3 polymorphisms predict circulating IGF levels but not breast cancer risk: findings from the Breast and Prostate Cancer Cohort Consortium (BPC3). PLoS One 2008; 3: e2578.

    ArticleĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  49. Verheus M, McKay JD, Kaaks R, Canzian F, Biessy C, Johansson M et al. Common genetic variation in the IGF-1 gene, serum IGF-I levels and breast density. Breast Cancer Res Treat 2008; 112: 109ā€“122.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  50. 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: 880ā€“888.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  51. Neuhausen SL, Brummel S, Ding YC, Singer CF, Pfeiler G, Lynch HT et al. Genetic variation in insulin-like growth factor signaling genes and breast cancer risk among BRCA1 and BRCA2 carriers. Breast Cancer Res 2009; 11: R76.

    ArticleĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

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Acknowledgements

This work was funded by the NIH grant 5 P30CA14089-27I and the Dhont Family Foundation. It was performed in the Sharon A Carpenter Laboratory at USC/Norris Comprehensive Cancer Center and in memory of David Donaldson.

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Correspondence to H-J Lenz.

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This work was previously presented at ASCO 2011 (J Clin Oncol 29: 2011 (suppl; abstr 538)).

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Winder, T., Giamas, G., Wilson, P. et al. Insulin-like growth factor receptor polymorphism defines clinical outcome in estrogen receptor-positive breast cancer patients treated with tamoxifen. Pharmacogenomics J 14, 28ā€“34 (2014). https://doi.org/10.1038/tpj.2013.8

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