A novel candidate metastasis modifier, ribosomal RNA processing 1 homolog B (Rrp1b), was identified through two independent approaches. First, yeast two-hybrid, immunoprecipitation, and functional assays demonstrated a physical and functional interaction between Rrp1b and the previous identified metastasis modifier Sipa1. In parallel, using mouse and human metastasis gene expression data it was observed that extracellular matrix (ECM) genes are common components of metastasis predictive signatures, suggesting that ECM genes are either important markers or causal factors in metastasis. To investigate the relationship between ECM genes and poor prognosis in breast cancer, expression quantitative trait locus analysis of polyoma middle-T transgene-induced mammary tumor was performed. ECM gene expression was found to be consistently associated with Rrp1b expression. In vitro expression of Rrp1b significantly altered ECM gene expression, tumor growth, and dissemination in metastasis assays. Furthermore, a gene signature induced by ectopic expression of Rrp1b in tumor cells predicted survival in a human breast cancer gene expression dataset. Finally, constitutional polymorphism within RRP1B was found to be significantly associated with tumor progression in two independent breast cancer cohorts. These data suggest that RRP1B may be a novel susceptibility gene for breast cancer progression and metastasis.
References
[1]
Jemal A, Tiwari RC, Murray T, Ghafoor A, Samuels A, et al. (2004) Cancer statistics, 2004. CA Cancer J Clin 54: 8–29.
[2]
Guarneri V, Conte PF (2004) The curability of breast cancer and the treatment of advanced disease. Eur J Nucl Med Mol Imaging 31(Suppl 1): S149–S161.
[3]
Lifsted T, Le Voyer T, Williams M, Muller W, Klein-Szanto A, et al. (1998) Identification of inbred mouse strains harboring genetic modifiers of mammary tumor age of onset and metastatic progression. Int J Cancer 77: 640–644.
[4]
Guy CT, Cardiff RD, Muller WJ (1992) Induction of mammary tumors by expression of polyomavirus middle T oncogene: a transgenic mouse model for metastatic disease. Mol Cell Biol 12: 954–961.
[5]
Hunter KW, Broman KW, Voyer TL, Lukes L, Cozma D, et al. (2001) Predisposition to efficient mammary tumor metastatic progression is linked to the breast cancer metastasis suppressor gene Brms1. Cancer Res 61: 8866–8872.
[6]
Lancaster M, Rouse J, Hunter KW (2005) Modifiers of mammary tumor progression and metastasis on mouse chromosomes 7, 9, and 17. Mamm Genome 16: 120–126.
[7]
Park YG, Zhao X, Lesueur F, Lowy DR, Lancaster M, et al. (2005) Sipa1 is a candidate for underlying the metastasis efficiency modifier locus Mtes1. Nat Genet 37: 1055–1062.
[8]
Crawford NP, Ziogas A, Peel DJ, Hess J, Anton-Culver H, et al. (2006) Polymorphisms of SIPA1 are associated with metastasis and other indicators of poor prognosis in breast cancer. Breast Cancer Res 8: R16.
[9]
Ramaswamy S, Ross KN, Lander ES, Golub TR (2003) A molecular signature of metastasis in primary solid tumors. Nat Genet 33: 49–54.
[10]
van't Veer LJ, Dai H, van de Vijver MJ, He YD, Hart AA, et al. (2002) Gene expression profiling predicts clinical outcome of breast cancer. Nature 415: 530–536.
[11]
van de Vijver MJ, He YD, van't Veer LJ, Dai H, Hart AA, et al. (2002) A gene-expression signature as a predictor of survival in breast cancer. N Engl J Med 347: 1999–2009.
[12]
Yang H, Rouse J, Lukes L, Lancaster M, Veenstra T, et al. (2004) Caffeine suppresses metastasis in a transgenic mouse model: a prototype molecule for prophylaxis of metastasis. Clin Exp Metastasis 21: 719–735.
[13]
Yang H, Crawford N, Lukes L, Finney R, Lancaster M, et al. (2005) Metastasis predictive signature profiles pre-exist in normal tissues. Clin Exp Metastasis 22: 593–603.
[14]
Mucenski ML, Taylor BA, Jenkins NA, Copeland NG (1986) AKXD recombinant inbred strains: models for studying the molecular genetic basis of murine lymphomas. Mol Cell Biol 6: 4236–4243.
[15]
Wang J, Williams RW, Manly KF (2003) WebQTL: web-based complex trait analysis. Neuroinformatics 1: 299–308.
[16]
Chesler EJ, Lu L, Shou S, Qu Y, Gu J, et al. (2005) Complex trait analysis of gene expression uncovers polygenic and pleiotropic networks that modulate nervous system function. Nat Genet 37: 233–242.
[17]
Schadt EE, Lamb J, Yang X, Zhu J, Edwards S, et al. (2005) An integrative genomics approach to infer causal associations between gene expression and disease. Nat Genet 37: 710–717.
[18]
Pei XF, Noble MS, Davoli MA, Rosfjord E, Tilli MT, et al. (2004) Explant-cell culture of primary mammary tumors from MMTV-c-Myc transgenic mice. In Vitro Cell Dev Biol Anim 40: 14–21.
[19]
Aslakson CJ, Miller FR (1992) Selective events in the metastatic process defined by analysis of the sequential dissemination of subpopulations of a mouse mammary tumor. Cancer Res 52: 1399–1405.
[20]
Bild AH, Yao G, Chang JT, Wang Q, Potti A, et al. (2006) Oncogenic pathway signatures in human cancers as a guide to targeted therapies. Nature 439: 353–357.
[21]
Bystrykh L, Weersing E, Dontje B, Sutton S, Pletcher MT, et al. (2005) Uncovering regulatory pathways that affect hematopoietic stem cell function using ‘genetical genomics'. Nat Genet 37: 225–232.
[22]
Roepman P, Kemmeren P, Wessels LF, Slootweg PJ, Holstege FC (2006) Multiple robust signatures for detecting lymph node metastasis in head and neck cancer. Cancer Res 66: 2361–2366.
[23]
Dai H, van't Veer L, Lamb J, He YD, Mao M, et al. (2005) A cell proliferation signature is a marker of extremely poor outcome in a subpopulation of breast cancer patients. Cancer Res 65: 4059–4066.
[24]
Ivshina AV, George J, Senko O, Mow B, Putti TC, et al. (2006) Genetic reclassification of histologic grade delineates new clinical subtypes of breast cancer. Cancer Res 66: 10292–10301.
[25]
Carey LA, Perou CM, Livasy CA, Dressler LG, Cowan D, et al. (2006) Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study. JAMA 295: 2492–2502.
[26]
Hattori M, Tsukamoto N, Nur-e-Kamal MS, Rubinfeld B, Iwai K, et al. (1995) Molecular cloning of a novel mitogen-inducible nuclear protein with a Ran GTPase-activating domain that affects cell cycle progression. Mol Cell Biol 15: 552–560.
[27]
Kurachi H, Wada Y, Tsukamoto N, Maeda M, Kubota H, et al. (1997) Human SPA-1 gene product selectively expressed in lymphoid tissues is a specific GTPase-activating protein for Rap1 and Rap2. Segregate expression profiles from a rap1GAP gene product. J Biol Chem 272: 28081–28088.
[28]
Tsukamoto N, Hattori M, Yang H, Bos JL, Minato N (1999) Rap1 GTPase-activating protein SPA-1 negatively regulates cell adhesion. J Biol Chem 274: 18463–18469.
[29]
Ohba Y, Ikuta K, Ogura A, Matsuda J, Mochizuki N, et al. (2001) Requirement for C3G-dependent Rap1 activation for cell adhesion and embryogenesis. EMBO J 20: 3333–3341.
[30]
Yajnik V, Paulding C, Sordella R, McClatchey AI, Saito M, et al. (2003) DOCK4, a GTPase activator, is disrupted during tumorigenesis. Cell 112: 673–684.
[31]
Retta SF, Balzac F, Avolio M (2006) Rap1: a turnabout for the crosstalk between cadherins and integrins. Eur J Cell Biol 85: 283–293.
[32]
Savino TM, Bastos R, Jansen E, Hernandez-Verdun D (1999) The nucleolar antigen Nop52, the human homologue of the yeast ribosomal RNA processing RRP1, is recruited at late stages of nucleologenesis. J Cell Sci 112(Pt 12): 1889–1900.
[33]
Lehner B, Sanderson CM (2004) A protein interaction framework for human mRNA degradation. Genome Res 14: 1315–1323.
[34]
Feghali CA, Wright TM (1999) Identification of multiple, differentially expressed messenger RNAs in dermal fibroblasts from patients with systemic sclerosis. Arthritis Rheum 42: 1451–1457.
[35]
Park YG, Clifford R, Buetow KH, Hunter KW (2003) Multiple cross and inbred strain haplotype mapping of complex-trait candidate genes. Genome Res 13: 118–121.
[36]
Gorelenkov V, Antipov A, Lejnine S, Daraselia N, Yuryev A (2001) Set of novel tools for PCR primer design. Biotechniques 31: 1326–1330.
[37]
Crawford NP, Colliver DW, Funke AA, Young MN, Kelley S, et al. (2005) Characterization of genotype-phenotype relationships and stratification by the CARD15 variant genotype for inflammatory bowel disease susceptibility loci using multiple short tandem repeat genetic markers. Hum Mutat 25: 156–166.
[38]
Hedenfalk I, Duggan D, Chen Y, Radmacher M, Bittner M, et al. (2001) Gene-expression profiles in hereditary breast cancer. N Engl J Med 344: 539–548.
[39]
Ross DT, Scherf U, Eisen MB, Perou CM, Rees C, et al. (2000) Systematic variation in gene expression patterns in human cancer cell lines. Nat Genet 24: 227–235.
[40]
Ziogas A, Gildea M, Cohen P, Bringman D, Taylor TH, et al. (2000) Cancer risk estimates for family members of a population-based family registry for breast and ovarian cancer. Cancer Epidemiol Biomarkers Prev 9: 103–111.
[41]
Carlson CS, Eberle MA, Rieder MJ, Yi Q, Kruglyak L, et al. (2004) Selecting a maximally informative set of single-nucleotide polymorphisms for association analyses using linkage disequilibrium. Am J Hum Genet 74: 106–120.
[42]
Barrett JC, Fry B, Maller J, Daly MJ (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21: 263–265.
