TY - JOUR
T1 - Genetic polymorphisms in the long noncoding RNA MIR2052HG offer a pharmacogenomic basis for the response of breast cancer patients to aromatase inhibitor therapy
AU - Ingle, James N.
AU - Xie, Fang
AU - Ellis, Matthew J.
AU - Goss, Paul E.
AU - Shepherd, Lois E.
AU - Chapman, Judith Anne W.
AU - Chen, Bingshu E.
AU - Kubo, Michiaki
AU - Furukawa, Yoichi
AU - Momozawa, Yukihide
AU - Stearns, Vered
AU - Pritchard, Kathleen I.
AU - Barman, Poulami
AU - Carlson, Erin E.
AU - Goetz, Matthew P.
AU - Weinshilboum, Richard M.
AU - Kalari, Krishna R.
AU - Wang, Liewei
N1 - Funding Information:
V. Stearns reports receiving a commercial research grant from Celgene, Merck, Medimmune, Abbvie, Novartis, Pfizer and Puma. M.P. Goetz is a consultant/advisory board member for Lilly. No potential conflicts of interest were disclosed by the other authors. The authors acknowledge the women who participated in the MA.27 clinical trial and provided DNA and consent for its use in genetic studies. These studies were supported in part by NIH grants U19 GM61388 (The Pharmacogenomics Research Network), P50CA116201 (Mayo Clinic Breast Cancer Specialized Program of Research Excellence), U10CA77202, R01CA196648, CCS 015469 from the Canadian Cancer Society, the Breast Cancer Research Foundation, and the RIKEN Center for Integrative Medical Science and the Biobank Japan Project funded by the Ministry of Education, Culture, Sports, Science and Technology, Japan. The MA.27 trial was supported, in part, by Pfizer, Inc. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
PY - 2016/12/1
Y1 - 2016/12/1
N2 - Genetic risks in breast cancer remain only partly understood. Here, we report the results of a genome-wide association study of germline DNA from 4,658 women, including 252 women experiencing a breast cancer recurrence, who were entered on the MA.27 adjuvant trial comparing the aromatase inhibitors (AI) anastrozole and exemestane. Single-nucleotide polymorphisms (SNP) of top significance were identified in the gene encoding MIR2052HG, a long noncoding RNA of unknown function. Heterozygous or homozygous individuals for variant alleles exhibited a ∼40% or ∼63% decrease, respectively, in the hazard of breast cancer recurrence relative to homozygous wild-type individuals. Functional genomic studies in lymphoblastoid cell lines and ERα-positive breast cancer cell lines showed that expression from MIR2052HG and the ESR1 gene encoding estrogen receptor-α (ERα) was induced by estrogen and AI in a SNP-dependent manner. Variant SNP genotypes exhibited increased ERα binding to estrogen response elements, relative to wild-type genotypes, a pattern that was reversed by AI treatment. Further, variant SNPs were associated with lower expression of MIR2052HG and ERα. RNAi-mediated silencing of MIR2052HG in breast cancer cell lines decreased ERα expression, cell proliferation, and anchorage-independent colony formation. Mechanistic investigations revealed that MIR2052HG sustained ERα levels both by promoting AKT/FOXO3-mediated ESR1 transcription and by limiting ubiquitin-mediated, proteasome-dependent degradation of ERα. Taken together, our results define MIR2052HS as a functionally polymorphic gene that affects risks of breast cancer recurrence in women treated with AI. More broadly, our results offer a pharmacogenomic basis to understand differences in the response of breast cancer patients to AI therapy.
AB - Genetic risks in breast cancer remain only partly understood. Here, we report the results of a genome-wide association study of germline DNA from 4,658 women, including 252 women experiencing a breast cancer recurrence, who were entered on the MA.27 adjuvant trial comparing the aromatase inhibitors (AI) anastrozole and exemestane. Single-nucleotide polymorphisms (SNP) of top significance were identified in the gene encoding MIR2052HG, a long noncoding RNA of unknown function. Heterozygous or homozygous individuals for variant alleles exhibited a ∼40% or ∼63% decrease, respectively, in the hazard of breast cancer recurrence relative to homozygous wild-type individuals. Functional genomic studies in lymphoblastoid cell lines and ERα-positive breast cancer cell lines showed that expression from MIR2052HG and the ESR1 gene encoding estrogen receptor-α (ERα) was induced by estrogen and AI in a SNP-dependent manner. Variant SNP genotypes exhibited increased ERα binding to estrogen response elements, relative to wild-type genotypes, a pattern that was reversed by AI treatment. Further, variant SNPs were associated with lower expression of MIR2052HG and ERα. RNAi-mediated silencing of MIR2052HG in breast cancer cell lines decreased ERα expression, cell proliferation, and anchorage-independent colony formation. Mechanistic investigations revealed that MIR2052HG sustained ERα levels both by promoting AKT/FOXO3-mediated ESR1 transcription and by limiting ubiquitin-mediated, proteasome-dependent degradation of ERα. Taken together, our results define MIR2052HS as a functionally polymorphic gene that affects risks of breast cancer recurrence in women treated with AI. More broadly, our results offer a pharmacogenomic basis to understand differences in the response of breast cancer patients to AI therapy.
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U2 - 10.1158/0008-5472.CAN-16-1371
DO - 10.1158/0008-5472.CAN-16-1371
M3 - Article
C2 - 27758888
AN - SCOPUS:85003018127
VL - 76
SP - 7012
EP - 7023
JO - Cancer Research
JF - Cancer Research
SN - 0008-5472
IS - 23
ER -