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A Risk Variant in an miR-125b Binding Site in BMPR1B Is Associated with Breast Cancer Pathogenesis
Open accessPublished version of a preprint
Abstract
MicroRNAs regulate diverse cellular processes and play an integral role in cancer pathogenesis. Genomic variation within miRNA target sites may therefore be important sources for genetic differences in cancer risk. To investigate this possibility, we mapped HapMap single nucleotide polymorphisms (SNP) to putative miRNA recognition sites within genes dysregulated in estrogen receptor-stratified breast tumors and used local linkage disequilibrium patterns to identify high-ranking SNPs in the Cancer Genetic Markers of Susceptibility (CGEMS) breast cancer genome-wide association study for further testing. Two SNPs, rs1970801 and rs11097457, scoring in the top 100 from the CGEMS study, were in strong linkage disequilibrium with rs1434536, an SNP that resides within a miR-125b target site in the 3' untranslated region of the bone morphogenic receptor type 1B (BMPR1B) gene encoding a transmembrane serine/threonine kinase. We validated the CGEMS association findings for rs1970801 in an independent cohort of admixture-corrected cases identified from families with multiple case histories. Subsequent association testing of rs1434536 for these cases and CGEMS controls with imputed genotypes supported the association. Furthermore, luciferase reporter assays and overexpression of miR-125b-mimics combined with quantitative reverse transcription-PCR showed that BMPR1B transcript is a direct target of miR-125b and that miR-125b differentially regulates the C and T alleles of rs1434536. These results suggest that allele-specific regulation of BMPR1B by miR-125b explains the observed disease risk. Our approach is general and can help identify and explain the mechanisms behind disease association for alleles that affect miRNA regulation.
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“current target prediction algorithms often identify many false positive target genes and there is no strong overlap in the predicted target gene list among prediction algorithms [138-141].”
From MicroRNAs in brain cholesterol metabolism and their implications for Alzheimer's disease (2016) · cites this paper as [141]
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Citations
Cites
The functions of animal microRNAs
Ambros, V. (2004) · Nature · doi:10.1038/nature02871 · Cited by 10,728 · cited 2×
“(1, 142) and seeded the analysis with a training set of 270 HapMap reference samples (CEU, YRI, and CHB+JTP) to perform STRUCTURE analysis with k = 3”
BackgroundMethodGenome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls
The Wellcome Trust Case Control Consortium, Management Committee, Burton, P. R., Clayton, D. G., Cardon, L. R., Craddock, N., Deloukas, P., Duncanson, A., Kwiatkowski, D. P., McCarthy, M. I., et al. (2007) · Nature · doi:10.1038/nature05911 · Cited by 9,442 · cited 2×
“In addition, the use of shared controls has recently been described for multiple common disease scenarios (9, 25, 26).”
BackgroundOncomirs—MicroRNAs with a role in cancer
Esquela-Kerscher, A., & Slack, F. J. (2006) · Nature Reviews Cancer · doi:10.1038/nrc1840 · Cited by 5,884 · cited 1×
“Functional studies indicate that changes in miRNA expression patterns might underlie human pathologies, including malignancies (3, 4).”
BackgroundMicroRNA Gene Expression Deregulation in Human Breast Cancer
Iorio, M. V., Ferracin, M., Liu, C.-G., Veronese, A., Spizzo, R., Sabbioni, S., Magri, E., Pedriali, M., Fabbri, M., Campiglio, M., et al. (2005) · Cancer Research · doi:10.1158/0008-5472.can-05-1783 · Cited by 4,053 · cited 2×
“Additionally, the overall luciferase activities observed were lower in MDA-MB-231 cells relative to MCF-7 cells, which may reflect the higher levels of miR-125b in this cell line (22).”
BackgroundResultMicroRNA Targeting Specificity in Mammals: Determinants beyond Seed Pairing
Grimson, A., Farh, K. K.-H., Johnston, W. K., Garrett-Engele, P., Lim, L. P., & Bartel, D. P. (2007) · Molecular Cell · doi:10.1016/j.molcel.2007.06.017 · Cited by 3,766 · cited 2×
“More specifically, we based our miRNA target site predictions on 7mer seed sites as we expected these would give an acceptable tradeoff between the number of false-negative and false-positive predictions (21).”
BackgroundMethodAccurate whole human genome sequencing using reversible terminator chemistry
Bentley, D. R., Balasubramanian, S., Swerdlow, H. P., Smith, G. P., Milton, J., Brown, C. G., Hall, K. P., Evers, D. J., Barnes, C. L., Bignell, H. R., et al. (2008) · Nature · doi:10.1038/nature07517 · Cited by 3,684 · cited 1×
“In addition, approaches such as whole genome sequencing and the identification of common recurrent somatic mutations in breast tumors may provide a large collection of potential disease alleles for exploration (39, 40).”
BackgroundGenome-wide association studies for complex traits: consensus, uncertainty and challenges
McCarthy, M. I., Abecasis, G. R., Cardon, L. R., Goldstein, D. B., Little, J., Ioannidis, J. P. A., & Hirschhorn, J. N. (2008) · Nature Reviews Genetics · doi:10.1038/nrg2344 · Cited by 2,891 · cited 1×
“This illustrates a common deficiency of GWAS data sets: the absence of low frequency/rare SNPs that may also play a role in disease risk (32).”
BackgroundThe Genomic Landscapes of Human Breast and Colorectal Cancers
Wood, L. D., Parsons, D. W., Jones, S., Lin, J., Sjöblom, T., Leary, R. J., Shen, D., Boca, S. M., Barber, T., Ptak, J., et al. (2007) · Science · doi:10.1126/science.1145720 · Cited by 2,833 · cited 1×
“In addition, approaches such as whole genome sequencing and the identification of common recurrent somatic mutations in breast tumors may provide a large collection of potential disease alleles for exploration (39, 40).”
BackgroundSelf-citationA new multipoint method for genome-wide association studies by imputation of genotypes
Marchini, J., Howie, B., Myers, S., McVean, G., & Donnelly, P. (2007) · Nature Genetics · doi:10.1038/ng2088 · Cited by 2,609 · cited 1×
“determination and association testing of rs1434536 as described (19).”
BackgroundThe role of site accessibility in microRNA target recognition
Kertesz, M., Iovino, N., Unnerstall, U., Gaul, U., & Segal, E. (2007) · Nature Genetics · doi:10.1038/ng2135 · Cited by 2,460 · cited 1×
“The algorithm models miRNA targeting as a competition between the free energy gained by miRNA binding and the energetic cost of displacing existing RNA secondary structure at the target site (28).”
Genome-wide association study identifies novel breast cancer susceptibility loci
Easton, D. F., Pooley, K. A., Dunning, A. M., Pharoah, P. D. P., Thompson, D., Ballinger, D. G., Struewing, J. P., Morrison, J., Field, H., Luben, R., et al. (2007) · Nature · doi:10.1038/nature05887 · Cited by 2,319
The Diverse Functions of MicroRNAs in Animal Development and Disease
Kloosterman, W. P., & Plasterk, R. H. A. (2006) · Developmental Cell · doi:10.1016/j.devcel.2006.09.009 · Cited by 2,082 · cited 1×
“MicroRNAs (miRNA) are a recently discovered class of short noncoding RNA genes that act posttranscriptionally as negative regulators of gene expression and play fundamental roles in cell growth, apoptosis, hematopoietic lineage differentiation, and differentiation (1, 2).”
BackgroundRioux, J. D., Xavier, R. J., Taylor, K. D., Silverberg, M. S., Goyette, P., Huett, A., Green, T., Kuballa, P., Barmada, M. M., Datta, L. W., et al. (2007) · Nature Genetics · doi:10.1038/ng2032 · Cited by 1,769 · cited 1×
“chemistry according to manufacturer’s instructions (17).”
Self-citationHunter, D. J., Kraft, P. L., Jacobs, K. B., Cox, D. G., Yeager, M., Hankinson, S. E., Wacholder, S., Wang, Z., Welch, R. A., Hutchinson, A. A., et al. (2007) · Nature Genetics · doi:10.1038/ng2075 · Cited by 1,487 · cited 1×
“Genome-wide association studies (GWAS) have been used in many common diseases to identify SNPs associated with disease (9, 10).”
BackgroundImpaired microRNA processing enhances cellular transformation and tumorigenesis
Kumar, M. S., Lü, J., Mercer, K. L., Golub, T. R., & Jacks, T. (2007) · Nature Genetics · doi:10.1038/ng2003 · Cited by 1,485 · cited 1×
“Functional studies indicate that changes in miRNA expression patterns might underlie human pathologies, including malignancies (3, 4).”
BackgroundGenes mirror geography within Europe
Novembre, J., Johnson, T., Bryc, K., Kutalik, Z., Boyko, A. R., Auton, A., Indap, A., King, K. S., Bergmann, S., Nelson, M. R., et al. (2008) · Nature · doi:10.1038/nature07331 · Cited by 1,479 · cited 1×
“More subtle levels of admixture within both European and Chinese populations have recently been described which will necessitate the continued use of extended AIM panels to discern finer levels of population substructure as a prelude to association testing and biological testing [33–35].”
BackgroundMicroRNA expression profiling of human breast cancer identifies new markers of tumor subtype
Blenkiron, C., Goldstein, L. D., Thorne, N., Spiteri, I., Chin, S., Dunning, M., Barbosa‐Morais, N. L., Teschendorff, A. E., Green, A. R., Ellis, I. O., et al. (2007) · Genome biology · doi:10.1186/gb-2007-8-10-r214 · Cited by 974 · cited 2×
“ER− tumors in particular [22–24].”
BackgroundStacey, S. N., Manolescu, A., Sulem, P., Rafnar, T., Gudmundsson, J., Gudjonsson, S. A., Masson, G., Jakobsdottir, M., Thorlacius, S., Helgason, A., et al. (2007) · Nature Genetics · doi:10.1038/ng2064 · Cited by 786 · cited 1×
“To date, four independent studies examining BrCa patients have identified multiple SNPs associated with disease [10–13].”
BackgroundMattie, M. D., Benz, C. C., Bowers, J., Sensinger, K., Wong, L., Scott, G. K., Fedele, V., Ginzinger, D. G., Getts, R. C., & Haqq, C. (2006) · Molecular Cancer · doi:10.1186/1476-4598-5-24 · Cited by 711
Two independent alleles at 6q23 associated with risk of rheumatoid arthritis
Plenge, R. M., Cotsapas, C. J., Davies, L. R. L., Price, A. L., de Bakker, P. I. W., Maller, J., Pe’er, I., Burtt, N. P., Blumenstiel, B. S., DeFelice, M., et al. (2007) · Nature Genetics · doi:10.1038/ng.2007.27 · Cited by 552 · cited 1×
“In addition, the use of shared controls has recently been described for multiple common disease scenarios (9, 25, 26).”
BackgroundSelf-citationKosoy, R., Nassir, R., Tian, C., White, P. A., Butler, L. M., SILVA, G. H. D. O., Kittles, R. A., Alarcón-Riquelme, M. E., Gregersen, P. K., Belmont, J. W., et al. (2008) · Human Mutation · doi:10.1002/humu.20822 · Cited by 539 · cited 2×
“We selected 59 AIMs (Supplementary Table S2) based on the 64 most informative In4 markers as described by Kosoy and colleagues (18) for population structure analysis.”
MethodSignal transduction by bone morphogenetic proteins
Kawabata, M. (1998) · Cytokine & Growth Factor Reviews · doi:10.1016/s1359-6101(97)00036-1 · Cited by 530 · cited 1×
“Once activated, BMP/receptor complexes phosphorylate cytosolic SMAD proteins that translocate to nucleus and regulate target genes (31).”
BackgroundAdams, B. D., Furneaux, H., & White, B. A. (2007) · Molecular Endocrinology · doi:10.1210/me.2007-0022 · Cited by 484 · cited 2×
“Allelic variation at this SNP was shown to influence ESR expression over 3-fold in HeLa cells [20].”
BackgroundOverview of Bone Morphogenetic Proteins
Wozney, J. M. (2002) · Spine · doi:10.1097/00007632-200208151-00002 · Cited by 414 · cited 1×
“BMPR1B binds bone morphogenetic proteins (BMP) and are multifunctional signaling molecules that belong to the transforming growth factor beta (TGF-β) superfamily and were first identified based on their ability to form bone at extraskeletal sites [30].”
BackgroundAccounting for ancestry: population substructure and genome-wide association studies
Tian, C., Gregersen, P. K., & Seldin, M. F. (2008) · Human Molecular Genetics · doi:10.1093/hmg/ddn268 · Cited by 375 · cited 2×
“To rectify this, it has been proposed that AIM panels should be used before GWA tests (26).”
BackgroundMethodGarcía‐Closas, M., Hall, P. N., Nevanlinna, H. A., Pooley, K. A., Morrison, J., Richesson, D. A., Bojesen, S. E., Nordestgaard, B. G., Axelsson, C. K., Arias, J. I., et al. (2008) · PLoS Genetics · doi:10.1371/journal.pgen.1000054 · Cited by 372 · cited 1×
“Replication studies of the very top tier signals in breast cancer have firmly established some associations; however, modest signals in first round GWAS screens may not be selected for rescreening (36).”
BackgroundGenome-wide association studies: potential next steps on a genetic journey
McCarthy, M. I., & Hirschhorn, J. N. (2008) · Human Molecular Genetics · doi:10.1093/hmg/ddn289 · Cited by 364 · cited 1×
“Our approach relies on integrating association data, expression profiles, and testable biological models to evaluate potential disease alleles in pathogenesis (38).”
MethodGenome-wide association study provides evidence for a breast cancer risk locus at 6q22.33
Gold, B., Kirchhoff, T., Stefanov, S. A., Lautenberger, J. A., Viale, A. J., Garber, J. E., Friedman, E., Narod, S. A., Olshen, A. B., Gregersen, P. K., et al. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0800441105 · Cited by 298 · cited 2×
“To date, four independent studies examining BrCa patients have identified multiple SNPs associated with disease [10–13].”
BackgroundPolymorphisms within micro-RNA-binding sites and risk of sporadic colorectal cancer
Landi, D., Gemignani, F., Naccarati, A., Pardini, B., Vodička, P., Vodičková, Ľ., Novotný, J. P., Försti, A., Hemminki, K., Canzian, F., et al. (2007) · Carcinogenesis · doi:10.1093/carcin/bgm304 · Cited by 276 · cited 1×
“In addition, variations in miRNA target sites mediated by single nucleotide polymorphisms (SNP) may be associated with human cancers (5, 6).”
BackgroundHalder, I., Shriver, M., Thomas, M., Fernandez, J. R., & Frudakis, T. (2008) · Human Mutation · doi:10.1002/humu.20695 · Cited by 274 · cited 1×
“Recently, AIMs useful for determining intercontinental admixture have been described to facilitate structured association testing in case-control studies (27).”
BackgroundYu, Z., Li, Z., Jolicoeur, N., Zhang, L., Fortin, Y., Wang, E., Wu, M., & Shen, S. (2007) · Nucleic Acids Research · doi:10.1093/nar/gkm480 · Cited by 259 · cited 1×
“In addition, variations in miRNA target sites mediated by single nucleotide polymorphisms (SNP) may be associated with human cancers (5, 6).”
BackgroundTworoger, S. S., Eliassen, A. H., Sluss, P. M., & Hankinson, S. E. (2007) · Journal of Clinical Oncology · doi:10.1200/jco.2006.07.6356 · Cited by 217 · cited 1×
“CGEMS patients consisted of 1,142 controls and 1,145 cases of post-menopausal BrCa and were gathered from the Nurses Health Study as described previously [10, 15].”
MethodAnalysis of East Asia Genetic Substructure Using Genome-Wide SNP Arrays
Tian, C., Kosoy, R., Lee, A., Ransom, M., Belmont, J. W., Gregersen, P. K., & Seldin, M. F. (2008) · PLoS ONE · doi:10.1371/journal.pone.0003862 · Cited by 114
Helms, M. W., Packeisen, J., August, C., Schittek, B., Boecker, W., Brandt, B., & Buerger, H. (2005) · The Journal of Pathology · doi:10.1002/path.1785 · Cited by 96 · cited 1×
“Consistent with this, increased BMPRIB expression is associated with high tumor grade, proliferation, cytogenetic instability, and a poor prognosis in ER+ breast carcinomas (29).”
BackgroundTrends in meta-analysis of genetic association studies
Zintzaras, E., & Lau, J. (2007) · Journal of Human Genetics · doi:10.1007/s10038-007-0223-5 · Cited by 87 · cited 1×
“Thus, we feel it is likely that future meta-analyses of multiple GWAS data sets will provide additional candidates for examination (37).”
BackgroundApplication of Ancestry Informative Markers to Association Studies in European Americans
Seldin, M. F., & Price, A. L. (2008) · PLoS Genetics · doi:10.1371/journal.pgen.0040005 · Cited by 61
Smith, D. D., Sætrom, P., Snøve, O., Lundberg, C. G., Rivas, G. E., Glackin, C. A., & Larson, G. P. (2008) · BMC Bioinformatics · doi:10.1186/1471-2105-9-63 · Cited by 47 · cited 4×
“these results, at least partly explain why ER+ tumors have increased BMPR1B expression (14).”
BackgroundResultInfluentialSelf-citationLoi, S., Piccart, M. J., & Sotiriou, C. P. (2006) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2006.09.005 · Cited by 45
An Allelic Variant at the ATM Locus Is Implicated in Breast Cancer Susceptibility
LARSON, G. P., ZHANG, G., DING, S., Foldenauer, K., Udar, N., Gatti, R. A., Neuberg, D. S., Lunetta, K. L., Ruckdeschel, J. C., Longmate, J., et al. (1997) · Genetic Testing · doi:10.1089/gte.1997.1.165 · Cited by 44 · cited 1×
“previously described from peripheral leukocytes (16).”
Self-citationGene-expression assays: New tools to individualize treatment of early-stage breast cancer
Dobbe, E., Gurney, K., Kiekow, S., Lafferty, J. S., & Kolesar, J. (2007) · American Journal of Health-System Pharmacy · doi:10.2146/ajhp060352 · Cited by 34 · cited 1×
“Gene expression profiling studies have identified specific signatures for breast cancer and are used to guide patient treatment with both the Oncotype Dx and Mammaprint tests in use clinically (7, 8).”
Method
Cited by
Sorted by citations
Genetic variation in microRNA networks: the implications for cancer research
Ryan, B. M., Robles, A. I., & Harris, C. C. (2010) · Nature reviews. Cancer · doi:10.1038/nrc2867 · Cited by 1,269
MicroRNAs in Development and Disease
Sayed, D. H., & Abdellatif, M. (2011) · Physiological Reviews · doi:10.1152/physrev.00006.2010 · Cited by 1,101
“(BMPR1B) (522) that are associated with breast cancer, confirms its role in the underlying pathogenesis.”
BackgroundOncomiR or Tumor Suppressor? The Duplicity of MicroRNAs in Cancer
Svoronos, A. A., Engelman, D. M., & Slack, F. J. (2016) · Cancer Research · doi:10.1158/0008-5472.can-16-0359 · Cited by 815
“Multiple studies have shown that mutations and single-nucleotide polymorphisms can result in the functional loss of existing miRNA target sites (13, 14), as well as the creation of new miRNA target sites (15).”
Signaling Receptors for TGF-β Family Members
Heldin, C.-H., & Moustakas, A. (2016) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a022053 · Cited by 711
Vitale, A. V., Tan, H., & Jin, P. (2011) · Journal of Nucleic Acids Investigation · doi:10.4081/jnai.2011.2236 · Cited by 626
“An A>G SNP is also found related BC, though its exact mechanism of action is unknown.(59) Another SNP, rs89519, was assessed with a reduction in BC within related individuals, though again the achievement of this SNP to aid in circumventing BC is a quandary.”
Background
Metadata
- Authors
- Sætrom, P., Biesinger, J., Li, S. M., Smith, D., Thomas, L. F., Majzoub, K., Rivas, G. E., Alluin, J., Rossi, J. J., Krontiris, T. G., Weitzel, J., Daly, M. B., Benson, A. B., Kirkwood, J. M., O'Dwyer, P. J., Sutphen, R., Stewart, J. A., Johnson, D., & Larson, G. P.
- Affiliations
- 1Cancer Research and Molecular Medicine and Departments of
- Brigham Young University (US)
- City Of Hope National Medical Center (US)
- 6Division of Molecular Biology, and Departments of
- 7Molecular Medicine and
- Beckman Research Institute (US)
- Fox Chase Cancer Center (US)
- Northwestern University (US)
- University of Pittsburgh (US)
- University of Pennsylvania (US)
- University of South Florida (US)
- University of Wisconsin–Madison (US)
- Vanderbilt University (US)
- Corresponding author
- Larson, Garrett P.
- ORCID
- Venue
- Cancer Research
- Published
- 2009-09-14
- Volume
- 69
- Issue
- 18
- Pages
- 7459-7465
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC2747041
- OpenAlex
- W2109029126
- Cited by
- 138
- References
- 41
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 2 · 2023: 2 · 2022: 3 · 2021: 5 · 2020: 5 · 2019: 6 · 2018: 6 · 2017: 8 · 2016: 12 · 2015: 10 · 2014: 12 · 2013: 12 · 2012: 19
- FWCI
- 5.93
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Science Foundation (0609454)
- Norges Forskningsråd
- National Institutes of Health (1rc4ca153828-01)
- National Heart, Lung, and Blood Institute (R01HL074704, HL074704)
- National Cancer Institute (R01CA106414, RC4-CA153828, U24CA114737)
- National Institute of Allergy and Infectious Diseases (P01AI046030)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer-related molecular mechanisms research
- Keywords
- breast cancer susceptibility, miR-125b, BMPR1B, microRNA binding sites, single nucleotide polymorphisms, 3' untranslated region, allele-specific gene regulation, linkage disequilibrium, estrogen receptor-positive breast cancer, microRNA target regulation
- MeSH terms
- Adolescent, Adult, Aged, Aged, 80 and over, Alleles, Binding Sites, Breast Neoplasms, Cell Transformation, Neoplastic, Female, Humans, Middle Aged, Receptors, Estrogen, Transfection, Gene Expression Regulation, Neoplastic, Polymorphism, Single Nucleotide, MicroRNAs, Cell Line, Tumor, Bone Morphogenetic Protein Receptors, Type I, Young Adult
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