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Novel insulin receptor substrate 1 and 2 variants in breast and colorectal cancer

  • Authors:
    • Diana Liberata Esposito
    • Fabio Verginelli
    • Sonia Toracchio
    • Sandra Mammarella
    • Laura De Lellis
    • Cinzia Vanni
    • Antonio Russo
    • Renato Mariani-Costantini
    • Alessandro Cama
  • View Affiliations / Copyright

    Affiliations: Unit of General Pathology, Aging Research Center, G. d'Annunzio University Foundation, I‑66100 Chieti, Italy, Department of Pharmacy, University G. d'Annunzio Chieti-Pescara, I‑66100 Chieti, Italy, Hospital SS Annunziata, Laboratory of Clinical Pathology, I‑66100 Chieti, Italy, University of Palermo, Department of Surgical and Oncological Sciences, I-90133 Palermo, Italy
    Copyright: © Esposito et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].
  • Pages: 1553-1560
    |
    Published online on: July 18, 2013
       https://doi.org/10.3892/or.2013.2626
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Abstract

The insulin/insulin-like growth factor pathway is involved in breast and colorectal cancer (CRC) development. In the present study, we analyzed the coding region and short intron-exon borders of the insulin receptor substrate 1 and 2 (IRS‑1 and IRS‑2) genes in 12 cell lines derived from breast cancer (BC), 14 cell lines derived from CRC and 33 primary CRCs. The nucleotide variants identified in BC were 3 in IRS‑1, 1 of which (p.Arg267Cys) was novel and with a pathogenic potential as predicted by in silico analysis and 6 in IRS‑2. Twenty‑one variants in IRS‑1 and 18 in IRS‑2 were identified in the CRC samples. These included 11 novel IRS‑1 variants detected exclusively in CRCs, which included 5 missense (p.Pro559Leu, p.Gln655His, p.Asp1014Gly, p.Asp1181His and pPro1203Ser) with a pathogenic potential as predicted by in silico analysis, 2 frameshifts predicted to generate a truncated protein, 1 splice-site mutation and 3 silent variants. In the CRC samples we also identified 7 novel IRS‑2 variants, including 4 missense variants, which included 2 (p.Asp782Asn and p.Gly1230Ser) with a pathogenic potential as predicted by in silico analysis, 2 frame insertion mutations and 1 silent variant. Most of the novel IRS‑1 and IRS‑2 variants may be involved in the modulation of IRS-1 or IRS‑2 functions and could be relevant to breast and colorectal tumorigenesis.
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1 

Sun XJ, Rothenberg P, Kahn CR, et al: Structure of the insulin receptor substrate IRS-1 defines a unique signal transduction protein. Nature. 352:73–77. 1991. View Article : Google Scholar : PubMed/NCBI

2 

Yamauchi T, Ueki K, Tobe K, et al: Growth hormone-induced tyrosine phosphorylation of EGF receptor as an essential element leading to MAP kinase activation and gene expression. Endocr J. 45(Suppl): S27–S31. 1998. View Article : Google Scholar : PubMed/NCBI

3 

White MF and Yenush L: The IRS-signaling system: a network of docking proteins that mediate insulin and cytokine action. Curr Top Microbiol Immunol. 228:179–208. 1998.

4 

Smith-Hall J, Pons S, Patti ME, et al: The 60 kDa insulin receptor substrate functions like an IRS protein (pp60IRS3) in adipose cells. Biochemistry. 36:8304–8310. 1997. View Article : Google Scholar : PubMed/NCBI

5 

Fantin VR, Sparling JD, Slot JW, Keller SR, Lienhard GE and Lavan BE: Characterization of insulin receptor substrate 4 in human embryonic kidney 293 cells. J Biol Chem. 273:10726–10732. 1998. View Article : Google Scholar : PubMed/NCBI

6 

White MF: IRS proteins and the common path to diabetes. Am J Physiol Endocrinol Metab. 283:E413–E422. 2002. View Article : Google Scholar : PubMed/NCBI

7 

Araki E, Lipes MA, Patti ME, et al: Alternative pathway of insulin signalling in mice with targeted disruption of the IRS-1 gene. Nature. 372:186–190. 1994. View Article : Google Scholar : PubMed/NCBI

8 

Withers DJ, Gutierrez JS, Towery H, et al: Disruption of IRS-2 causes type 2 diabetes in mice. Nature. 391:900–904. 1998. View Article : Google Scholar : PubMed/NCBI

9 

Slattery ML, Samowitz W, Curtin K, et al: Associations among IRS1, IRS2, IGF1, and IGFBP3 genetic polymorphisms and colorectal cancer. Cancer Epidemiol Biomarkers Prev. 13:1206–1214. 2004.PubMed/NCBI

10 

Ding YC, McGuffog L, Healey S, et al: A nonsynonymous polymorphism in IRS1 modifies risk of developing breast and ovarian cancers in BRCA1 and ovarian cancer in BRCA2 mutation carriers. Cancer Epidemiol Biomarkers Prev. 21:1362–1370. 2012. View Article : Google Scholar : PubMed/NCBI

11 

Esposito DL, Aru F, Lattanzio R, et al: The insulin receptor substrate 1 (IRS1) in intestinal epithelial differentiation and in colorectal cancer. PLoS One. 7:e361902012. View Article : Google Scholar : PubMed/NCBI

12 

Bommer GT, Feng Y, Iura A, et al: IRS1 regulation by Wnt/beta-catenin signaling and varied contribution of IRS1 to the neoplastic phenotype. J Biol Chem. 285:1928–1938. 2010. View Article : Google Scholar : PubMed/NCBI

13 

Ramocki NM, Wilkins HR, Magness ST, et al: Insulin receptor substrate-1 deficiency promotes apoptosis in the putative intestinal crypt stem cell region, limits Apcmin/+tumors, and regulates Sox9. Endocrinology. 149:261–267. 2008. View Article : Google Scholar : PubMed/NCBI

14 

Parsons DW, Wang TL, Samuels Y, et al: Colorectal cancer: mutations in a signalling pathway. Nature. 436:7922005. View Article : Google Scholar : PubMed/NCBI

15 

Bishehsari F, Mahdavinia M, Malekzadeh R, et al: Patterns of K-ras mutation in colorectal carcinomas from Iran and Italy (a Gruppo Oncologico dell’Italia Meridionale study): influence of microsatellite instability status and country of origin. Ann Onco. 17 Suppl 7:vii91–vii96. 2006.PubMed/NCBI

16 

Palmirotta R, Matera S, Curia MC, et al: Correlations between phenotype and microsatellite instability in HNPCC: implications for genetic testing. Fam Cancer. 3:117–121. 2004. View Article : Google Scholar : PubMed/NCBI

17 

Bottomley WE, Soos MA, Adams C, et al: IRS2 variants and syndromes of severe insulin resistance. Diabetologia. 52:1208–1211. 2009. View Article : Google Scholar : PubMed/NCBI

18 

Ng PC and Henikoff S: Predicting deleterious amino acid substitutions. Genome Res. 11:863–874. 2001. View Article : Google Scholar : PubMed/NCBI

19 

Xi T, Jones IM and Mohrenweiser HW: Many amino acid substitution variants identified in DNA repair genes during human population screenings are predicted to impact protein function. Genomics. 83:970–979. 2004. View Article : Google Scholar

20 

Almind K, Bjørbaek C, Vestergaard H, Hansen T, Echwald S and Pedersen O: Amino acid polymorphisms of insulin receptor substrate-1 in non-insulin-dependent diabetes mellitus. Lancet. 342:828–832. 1993. View Article : Google Scholar : PubMed/NCBI

21 

Laakso M, Malkki M, Kekäläinen P, Kuusisto J and Deeb SS: Insulin receptor substrate-1 variants in non-insulin-dependent diabetes. J Clin Invest. 94:1141–1146. 1994. View Article : Google Scholar : PubMed/NCBI

22 

Imai Y, Fusco A, Suzuki Y, et al: Variant sequences of insulin receptor substrate-1 in patients with noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab. 79:1655–1658. 1994.PubMed/NCBI

23 

Ura S, Araki E, Kishikawa H, et al: Molecular scanning of the insulin receptor substrate-1 (IRS-1) gene in Japanese patients with NIDDM: identification of five novel polymorphisms. Diabetologia. 39:600–608. 1996. View Article : Google Scholar : PubMed/NCBI

24 

Esposito DL, Mammarella S, Ranieri A, et al: Deletion of Gly723 in the insulin receptor substrate-1 of a patient with noninsulin-dependent diabetes mellitus. Hum Mutat. 7:364–366. 1996. View Article : Google Scholar : PubMed/NCBI

25 

Whitehead JP, Humphreys P, Krook A, et al: Molecular scanning of the insulin receptor substrate 1 gene in subjects with severe insulin resistance: detection and functional analysis of a naturally occurring mutation in a YMXM motif. Diabetes. 47:837–839. 1998. View Article : Google Scholar

26 

Celi FS, Negri C, Tanner K, et al: Molecular scanning for mutations in the insulin receptor substrate-1 (IRS-1) gene in Mexican Americans with type 2 diabetes mellitus. Diabetes Metab Res Rev. 16:370–377. 2000. View Article : Google Scholar : PubMed/NCBI

27 

Esposito DL, Li Y, Vanni C, et al: A novel T608R missense mutation in insulin receptor substrate-1 identified in a subject with type 2 diabetes impairs metabolic insulin signaling. J Clin Endocrinol Metab. 88:1468–1475. 2003. View Article : Google Scholar : PubMed/NCBI

28 

Abecasis GR, Altshuler D, Auton A, et al: A map of human genome variation from population-scale sequencing. Nature. 467:1061–1073. 2010. View Article : Google Scholar : PubMed/NCBI

29 

Bernal D, Almind K, Yenush L, et al: Insulin receptor substrate-2 amino acid polymorphisms are not associated with random type 2 diabetes among Caucasians. Diabetes. 47:976–979. 1998. View Article : Google Scholar : PubMed/NCBI

30 

Butte NF, Voruganti VS, Cole SA, et al: Resequencing of IRS2 reveals rare variants for obesity but not fasting glucose homeostasis in Hispanic children. Physiol Genomics. 43:1029–1037. 2011. View Article : Google Scholar : PubMed/NCBI

31 

Heinen CD, Richardson D, White R and Groden J: Microsatellite instability in colorectal adenocarcinoma cell lines that have full-length adenomatous polyposis coli protein. Cancer Res. 55:4797–4799. 1995.PubMed/NCBI

32 

Giannini G, Rinaldi C, Ristori E, et al: Mutations of an intronic repeat induce impaired MRE11 expression in primary human cancer with microsatellite instability. Oncogene. 23:2640–2647. 2004. View Article : Google Scholar : PubMed/NCBI

33 

van der Heijden MS, Brody JR, Elghalbzouri-Maghrani E, Zdzienicka MZ and Kern SE: Does tumorigenesis select for or against mutations of the DNA repair-associated genes BRCA2 and MRE11?: considerations from somatic mutations in microsatellite unstable (MSI) gastrointestinal cancers. BMC Genet. 7:32006.PubMed/NCBI

34 

Chang Q, Li Y, White MF, Fletcher JA and Xiao S: Constitutive activation of insulin receptor substrate 1 is a frequent event in human tumors: therapeutic implications. Cancer Res. 62:6035–6038. 2002.

35 

Dearth RK, Cui X, Kim HJ, et al: Mammary tumorigenesis and metastasis caused by overexpression of insulin receptor substrate 1 (IRS-1) or IRS-2. Mol Cell Biol. 26:9302–9314. 2006. View Article : Google Scholar : PubMed/NCBI

36 

Dearth RK, Cui X, Kim HJ, Hadsell DL and Lee AV: Oncogenic transformation by the signaling adaptor proteins insulin receptor substrate (IRS)-1 and IRS-2. Cell Cycle. 6:705–713. 2007. View Article : Google Scholar : PubMed/NCBI

37 

Houghton AM, Rzymkiewicz DM, Ji H, et al: Neutrophil elastase-mediated degradation of IRS-1 accelerates lung tumor growth. Nat Med. 16:219–223. 2010. View Article : Google Scholar : PubMed/NCBI

38 

Modica S, Morgano A, Salvatore L, et al: Expression and localisation of insulin receptor substrate 2 in normal intestine and colorectal tumours. Regulation by intestine-specific transcription factor CDX2. Gut. 58:1250–1259. 2009. View Article : Google Scholar : PubMed/NCBI

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Copy and paste a formatted citation
Spandidos Publications style
Esposito DL, Verginelli F, Toracchio S, Mammarella S, De Lellis L, Vanni C, Russo A, Mariani-Costantini R and Cama A: Novel insulin receptor substrate 1 and 2 variants in breast and colorectal cancer. Oncol Rep 30: 1553-1560, 2013.
APA
Esposito, D.L., Verginelli, F., Toracchio, S., Mammarella, S., De Lellis, L., Vanni, C. ... Cama, A. (2013). Novel insulin receptor substrate 1 and 2 variants in breast and colorectal cancer. Oncology Reports, 30, 1553-1560. https://doi.org/10.3892/or.2013.2626
MLA
Esposito, D. L., Verginelli, F., Toracchio, S., Mammarella, S., De Lellis, L., Vanni, C., Russo, A., Mariani-Costantini, R., Cama, A."Novel insulin receptor substrate 1 and 2 variants in breast and colorectal cancer". Oncology Reports 30.4 (2013): 1553-1560.
Chicago
Esposito, D. L., Verginelli, F., Toracchio, S., Mammarella, S., De Lellis, L., Vanni, C., Russo, A., Mariani-Costantini, R., Cama, A."Novel insulin receptor substrate 1 and 2 variants in breast and colorectal cancer". Oncology Reports 30, no. 4 (2013): 1553-1560. https://doi.org/10.3892/or.2013.2626
Copy and paste a formatted citation
x
Spandidos Publications style
Esposito DL, Verginelli F, Toracchio S, Mammarella S, De Lellis L, Vanni C, Russo A, Mariani-Costantini R and Cama A: Novel insulin receptor substrate 1 and 2 variants in breast and colorectal cancer. Oncol Rep 30: 1553-1560, 2013.
APA
Esposito, D.L., Verginelli, F., Toracchio, S., Mammarella, S., De Lellis, L., Vanni, C. ... Cama, A. (2013). Novel insulin receptor substrate 1 and 2 variants in breast and colorectal cancer. Oncology Reports, 30, 1553-1560. https://doi.org/10.3892/or.2013.2626
MLA
Esposito, D. L., Verginelli, F., Toracchio, S., Mammarella, S., De Lellis, L., Vanni, C., Russo, A., Mariani-Costantini, R., Cama, A."Novel insulin receptor substrate 1 and 2 variants in breast and colorectal cancer". Oncology Reports 30.4 (2013): 1553-1560.
Chicago
Esposito, D. L., Verginelli, F., Toracchio, S., Mammarella, S., De Lellis, L., Vanni, C., Russo, A., Mariani-Costantini, R., Cama, A."Novel insulin receptor substrate 1 and 2 variants in breast and colorectal cancer". Oncology Reports 30, no. 4 (2013): 1553-1560. https://doi.org/10.3892/or.2013.2626
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