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A risk variant in an miR-125b binding site in BMPR1B is associated with breast cancer pathogenesis.

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.

SUBMITTER: Saetrom P

PROVIDER: S-EPMC2747041 | biostudies-literature | 2009 Sep

REPOSITORIES: biostudies-literature

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A risk variant in an miR-125b binding site in BMPR1B is associated with breast cancer pathogenesis.

Saetrom Pål P Biesinger Jacob J Li Sierra M SM Smith David D Thomas Laurent F LF Majzoub Karim K Rivas Guillermo E GE Alluin Jessica J Rossi John J JJ Krontiris Theodore G TG Weitzel Jeffrey J Daly Mary B MB Benson Al B AB Kirkwood John M JM O'Dwyer Peter J PJ Sutphen Rebecca R Stewart James A JA Johnson David D Larson Garrett P GP

Cancer research 20090908 18

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 Cance ...[more]

PMID: 19738052

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Project description:BackgroundBone morphogenetic protein receptor I B (BMPR1B) is a transmembrane receptor mediating TGF-? signal transduction. Recent studies indicate a tumor suppressor role for BMPR1B in ovarian cancer. Polymorphism at BMPR1B 3'UTR within the miR-125b binding site alters its binding affinity toward the miRNA, which may result in insufficient post-transcriptional repression.MethodsSingle-nucleotide polymorphisms rs1970801, rs1434536, and rs11097457 near the miR-125b binding site in BMPR1B were genotyped by Taqman assay on 193 endometriosis patients and 202 healthy controls. BMPR1B and CA125 levels in ectopic endometrial tissues were evaluated by quantitative PCR and immunohistochemistry. Luciferase reporter assay was utilized to verify regulatory roles of BMPR1B 3'UTR with allelic variants of rs1434536 in a cell line model. Cell proliferation and migration were recorded, while expression of BMPR1B, CA125, glucocorticoid receptor (GCCR) and IL-1? were measured by quantitative PCR in endometrial cells transfected with wild-type or mutated miR-125b.ResultsThis study found two endometriosis-associated SNPs, rs1434536 (P?=?0.010) and rs1970801 (P?=?0.0087), located within and next to a miR-125b binding site on BMPR1B. Interestingly, patients with homozygous variant alleles at rs1434536 showed significantly lower serum CA125 levels. Immunohistochemistry staining further confirmed inverse correlation between BMPR1B and CA125 levels in three rs1434536 genotypes. Cell assays demonstrated the variant allele of rs1434536 up-regulating BMPR1B at both mRNA and protein levels, which negatively correlated with CA125 and IL-1? levels. Disruption of the binding between miR-125b and BMPR1B hampered abnormal cell proliferation.ConclusionsSNPs of BMPR1B within and next to the miR-125b binding site manifested strong correlation with endometriosis development in a Taiwanese cohort. Disrupting the binding of miR-125b toward BMPR1B would increase protein expression, diminishing abnormal cell proliferation as well as serum and cellular CA125 levels. Genetic variation at the miR-125b binding site may play functional roles to protect against endometriosis progression.

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A risk variant in an miR-125b binding site in BMPR1B is associated with breast cancer pathogenesis.

Publications

A risk variant in an miR-125b binding site in BMPR1B is associated with breast cancer pathogenesis.

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