An osteopontin promoter polymorphism is associated with aggressiveness in breast cancer

Ramchandani,Divya; Weber,Georg  F.

doi:10.3892/or.2013.2632

An osteopontin promoter polymorphism is associated with aggressiveness in breast cancer

Authors:
- Divya Ramchandani
- Georg F. Weber
View Affiliations

Affiliations: University of Cincinnati Academic Health Center, College of Pharmacy, Cincinnati, OH 45267-0004, USA
Published online on: July 23, 2013 https://doi.org/10.3892/or.2013.2632
Pages: 1860-1868

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Metastasis-related genes are deregulated in cancer by aberrant expression or splicing. Here, we analyzed polymorphic sites in the osteopontin promoter as potential contributors to aberrant expression in breast cancers. This study comprised 241 breast cancer specimens, for which DNA from normal surrounding tissue was available for 111, and 65 healthy breast samples. The polymorphic site in position -443 of the promoter was associated with tumor grade. As expected, there was no association between promoter single nucleotide polymorphisms (SNPs) and tumor stage or in situ carcinoma versus cancer, as stage and early transformation are determined by the sampling time more than by tumor genetics. In a subset of samples, osteopontin RNA expression levels had previously been obtained. The allelic distribution in positions -443 and -1748 was distinct between high and low expressors, confirming the importance of promoter SNPs. These two sites also form a haplotype. Osteopontin expression has been associated with breast cancer progression, regardless of the histological subtype of the cancer. Remarkably, the polymorphic site at -443, but not -1748 or -1776, showed differences between ER-positive and ER-negative breast cancers and between PR-positive and PR-negative breast cancers, but there was no association with HER2 status. In five cases, the genotype of the tumor was different from the genotype of the host, implying the possibility of somatic mutations in the osteopontin promoter that may affect expression. Our results corroborate that the osteopontin promoter SNPs -443 (rs11730582) and -1748 (rs2728127) are important for gene expression and breast cancer aggressiveness.

View Figures

View References

1	Weber GF and Ashkar S: Stress response genes: the genes that make cancer metastasize. J Mol Med. 78:404–408. 2000. View Article : Google Scholar : PubMed/NCBI
2	Weber GF: Molecular mechanisms of metastasis. Cancer Lett. 270:181–190. 2008. View Article : Google Scholar
3	Weber GF, Lett S and Haubein N: Osteopontin is a marker for cancer aggressiveness and patient survival. Br J Cancer. 103:861–869. 2010. View Article : Google Scholar : PubMed/NCBI
4	Weber GF, Lett GS and Haubein NC: Categorical meta-analysis of osteopontin as a clinical cancer marker. Oncol Rep. 25:433–441. 2011. View Article : Google Scholar : PubMed/NCBI
5	Weber GF: The cancer biomarker osteopontin: combination with other markers. Cancer Genomics Proteomics. 8:263–288. 2011.PubMed/NCBI
6	Mirza M, Shaughnessy E, Hurley JK, Vanpatten KA, Pestano GA, He B and Weber GF: Osteopontin-c is a selective marker for breast cancer. Int J Cancer. 122:889–897. 2008. View Article : Google Scholar : PubMed/NCBI
7	Sullivan J, Blair L, Alnajar A, Aziz T, Ng CY, Chipitsyna G, Gong Q, Witkiewicz A, Weber GF, Denhardt DT, Yeo CJ and Arafat HA: Expression of a prometastatic splice variant of osteopontin, OPNC, in human pancreatic ductal adenocarcinoma. Surgery. 146:232–240. 2009. View Article : Google Scholar : PubMed/NCBI
8	Tilli TM, Franco VF, Robbs BK, Wanderley JL, da Silva FR, de Mello KD, Viola JP, Weber GF and Gimba ER: Osteopontin-c splicing isoform contributes to ovarian cancer progression. Mol Cancer Res. 9:280–293. 2011. View Article : Google Scholar : PubMed/NCBI
9	He B, Mirza M and Weber GF: An osteopontin splice variant induces anchorage independence in human breast cancer cells. Oncogene. 25:2192–2202. 2006. View Article : Google Scholar : PubMed/NCBI
10	Senger DR, Asch BB, Smith BD, Perruzzi CA and Dvorak HF: A secreted phosphoprotein marker for neoplastic transformation of both epithelial and fibroblastic cells. Nature. 302:714–715. 1983. View Article : Google Scholar : PubMed/NCBI
11	Noda M, Yoon K, Prince CW, Butler WT and Rodan GA: Transcriptional regulation of osteopontin production in rat osteosarcoma cells by type β transforming growth factor. J Biol Chem. 263:13916–13921. 1988.PubMed/NCBI
12	Chambers AF, Behrend EI, Wilson SM and Denhardt DT: Induction of expression of osteopontin (OPN; secreted phosphoprotein) in metastatic, ras-transformed NIH 3T3 cells. Anticancer Res. 12:43–47. 1992.PubMed/NCBI
13	Zhang G, He B and Weber GF: Growth factor signaling induces metastasis genes in transformed cells: molecular connection between Akt kinase and osteopontin in breast cancer. Mol Cell Biol. 23:6507–6519. 2003. View Article : Google Scholar
14	Whalen KA, Weber GF, Benjamin TL and Schaffhausen BS: Polyomavirus middle T antigen induces the transcription of osteopontin, a gene important for migration of transformed cells. J Virol. 82:4946–4954. 2008. View Article : Google Scholar : PubMed/NCBI
15	Giacopelli F, Marciano R, Pistorio A, Catarsi P, Canini S, Karsenty G and Ravazzolo R: Polymorphisms in the osteopontin promoter affect its transcriptional activity. Physiol Genomics. 20:87–96. 2004. View Article : Google Scholar : PubMed/NCBI
16	Hummelshoj T, Ryder LP, Madsen HO, Odum N and Svejgaard A: A functional polymorphism in the Eta-1 promoter is associated with allele specific binding to the transcription factor Sp1 and elevated gene expression. Mol Immunol. 43:980–986. 2006.PubMed/NCBI
17	Deng QL, Ishii S and Sarai A: Binding site analysis of c-Myb: screening of potential binding sites by using the mutation matrix derived from systematic binding affinity measurements. Nucleic Acids Res. 24:766–774. 1996. View Article : Google Scholar
18	Schultz J, Lorenz P, Ibrahim SM, Kundt G, Gross G and Kunz M: The functional −443T/C osteopontin promoter polymorphism influences osteopontin gene expression in melanoma cells via binding of c-Myb transcription factor. Mol Carcinog. 48:14–23. 2009.
19	Zhao F, Chen X, Meng T, Hao B, Zhang Z and Zhang G: Genetic polymorphisms in the osteopontin promoter increases the risk of distance metastasis and death in Chinese patients with gastric cancer. BMC Cancer. 12:4772012. View Article : Google Scholar : PubMed/NCBI
20	Ashkar S, Weber GF, Panoutsakopoulou V, Sanchirico ME, Janssen M, Zawaideh S, Rittling S, Denhardt DT, Glimcher MJ and Cantor H: Eta-1 (osteopontin): an early component of type-1 (cell-mediated) immunity. Science. 287:860–864. 2000. View Article : Google Scholar : PubMed/NCBI
21	Shaker OG, Sadik NA and El-Dessouki A: Single-nucleotide polymorphism in the promoter region of the osteopontin gene at nucleotide −443 as a marker predicting the efficacy of pegylated interferon/ribavirin-therapy in Egyptians patients with chronic hepatitis C. Hum Immunol. 73:1039–1045. 2012.
22	Mochida S, Hashimoto M, Matsui A, Naito M, Inao M, Nagoshi S, Nagano M, Egashira T, Mishiro S and Fujiwara K: Genetic polymorphisms in promoter region of osteopontin gene may be a marker reflecting hepatitis activity in chronic hepatitis C patients. Biochem Biophys Res Commun. 313:1079–1085. 2004. View Article : Google Scholar : PubMed/NCBI
23	Cheema BS, Iyengar S, Ahluwalia TS, Kohli HS, Sharma R, Shah VN, Bhansali A, Sakhuja V and Khullar M: Association of an Osteopontin gene promoter polymorphism with susceptibility to diabetic nephropathy in Asian Indians. Clin Chim Acta. 413:1600–1604. 2012.
24	Trivedi T, Franek BS, Green SL, Kariuki SN, Kumabe M, Mikolaitis RA, Jolly M, Utset TO and Niewold TB: Osteopontin alleles are associated with clinical characteristics in systemic lupus erythematosus. J Biomed Biotechnol. 2011:8025812011. View Article : Google Scholar : PubMed/NCBI
25	Jiang Y, Yao M, Liu Q and Zhou C: OPN gene polymorphisms influence the risk of knee OA and OPN levels in synovial fluid in a Chinese population. Arthritis Res Ther. 15:R32013. View Article : Google Scholar : PubMed/NCBI
26	Naito M, Matsui A, Inao M, Nagoshi S, Nagano M, Ito N, Egashira T, Hashimoto M, Mishiro S, Mochida S and Fujiwara K: SNPs in the promoter region of the osteopontin gene as a marker predicting the efficacy of interferon-based therapies in patients with chronic hepatitis C. J Gastroenterol. 40:381–388. 2005. View Article : Google Scholar : PubMed/NCBI
27	Xu G, Sun W, He D, Wang L, Zheng W, Nie H, Ni L, Zhang D, Li N and Zhang J: Overexpression of osteopontin in rheumatoid synovial mononuclear cells is associated with joint inflammation, not with genetic polymorphism. J Rheumatol. 32:410–416. 2005.PubMed/NCBI
28	Gao B, Yasui T, Itoh Y, Li Z, Okada A, Tozawa K, Hayashi Y and Kohri K: Association of osteopontin gene haplotypes with nephrolithiasis. Kidney Int. 72:592–598. 2007. View Article : Google Scholar : PubMed/NCBI
29	Gögebakan B, Igci YZ, Arslan A, Igci M, Erturhan S, Oztuzcu S, Sen H, Demiryürek S, Arikoglu H, Cengiz B, Bayraktar R, Yurtseven C, Sarıca K and Demiryürek AT: Association between the T-593A and C6982T polymorphisms of the osteopontin gene and risk of developing nephrolithiasis. Arch Med Res. 41:442–448. 2010.PubMed/NCBI
30	Schmidt-Petersen K, Brand E, Telgmann R, Nicaud V, Hagedorn C, Labreuche J, Dördelmann C, Elbaz A, Gautier-Bertrand M, Fischer JW, Evans A, Morrison C, Arveiler D, Stoll M, Amarenco P, Cambien F, Paul M and Brand-Herrmann SM: Osteopontin gene variation and cardio/cerebrovascular disease phenotypes. Atherosclerosis. 206:209–215. 2009. View Article : Google Scholar : PubMed/NCBI
31	Hendig D, Arndt M, Szliska C, Kleesiek K and Götting C: SPP1 promoter polymorphisms: identification of the first modifier gene for pseudoxanthoma elasticum. Clin Chem. 53:829–836. 2007. View Article : Google Scholar
32	Pegoraro E, Hoffman EP, Piva L, Gavassini BF, Cagnin S, Ermani M, Bello L, Soraru G, Pacchioni B, Bonifati MD, Lanfranchi G, Angelini C, Kesari A, Lee I, Gordish-Dressman H, Devaney JM and McDonald CM; Cooperative International Neuromuscular Research Group. SPP1 genotype is a determinant of disease severity in Duchenne muscular dystrophy. Neurology. 76:219–226. 2011. View Article : Google Scholar
33	de las Fuentes L, Gu CC, Mathews SJ, Reagan JL, Ruthmann NP, Waggoner AD, Lai CF, Towler DA and Dávila-Román VG: Osteopontin promoter polymorphism is associated with increased carotid intima-media thickness. J Am Soc Echocardiogr. 21:954–960. 2008.PubMed/NCBI
34	Marciano R, D’Annunzio G, Minuto N, Pasquali L, Santamaria A, Di Duca M, Ravazzolo R and Lorini R: Association of alleles at polymorphic sites in the osteopontin encoding gene in young type 1 diabetic patients. Clin Immunol. 131:84–91. 2009. View Article : Google Scholar : PubMed/NCBI
35	D’Alfonso S, Barizzone N, Giordano M, Chiocchetti A, Magnani C, Castelli L, Indelicato M, Giacopelli F, Marchini M, Scorza R, Danieli MG, Cappelli M, Migliaresi S, Bigliardo B, Sabbadini MG, Baldissera E, Galeazzi M, Sebastiani GD, Minisola G, Ravazzolo R, Dianzani U and Momigliano-Richiardi P: Two single-nucleotide polymorphisms in the 5′ and 3′ ends of the osteopontin gene contribute to susceptibility to systemic lupus erythematosus. Arthritis Rheum. 52:539–547. 2005.
36	Chen J, Wu Q, Lu Y, Xu T, Huang Y, Ribas J, Ni X, Hu G, Huang F, Zhou L and Lu D: SPP1 promoter polymorphisms and glioma risk in a Chinese Han population. J Hum Genet. 55:456–461. 2010. View Article : Google Scholar : PubMed/NCBI
37	Barizzone N, Marchini M, Cappiello F, Chiocchetti A, Orilieri E, Ferrante D, Corrado L, Mellone S, Scorza R, Dianzani U and D’Alfonso S: Association of osteopontin regulatory polymorphisms with systemic sclerosis. Hum Immunol. 72:930–934. 2011. View Article : Google Scholar : PubMed/NCBI
38	Nakayama H, Nagai H, Matsumoto K, Oguro R, Sugimoto K, Kamide K, Ohishi M, Katsuya T, Okamoto H, Maeda M, Komamura K, Azuma J, Rakugi H and Fujio Y: Association between osteopontin promoter variants and diastolic dysfunction in hypertensive heart in the Japanese population. Hypertens Res. 34:1141–1146. 2011. View Article : Google Scholar : PubMed/NCBI