Genetic polymorphisms in the long noncoding RNA MIR2052HG offer a pharmacogenomic basis for the response of breast cancer patients to aromatase inhibitor therapy

James N. Ingle, Fang Xie, Matthew J. Ellis, Paul E. Goss, Lois E. Shepherd, Judith Anne W Chapman, Bingshu E. Chen, Michiaki Kubo, Yoichi Furukawa, Yukihide Momozawa, Vered Stearns, Kathleen I. Pritchard, Poulami Barman, Erin E. Carlson, Matthew P. Goetz, Richard M. Weinshilboum, Krishna R. Kalari, Liewei Wang

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)7012-7023
Number of pages12
JournalCancer Research
Volume76
Issue number23
DOIs
StatePublished - Dec 1 2016

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Long Noncoding RNA
Aromatase Inhibitors
Pharmacogenetics
Genetic Polymorphisms
Estrogen Receptors
Breast Neoplasms
Single Nucleotide Polymorphism
exemestane
Recurrence
Cell Line
Therapeutics
Estrogens
Genotype
Genes
Genome-Wide Association Study
Response Elements
Proteasome Endopeptidase Complex
Ubiquitin
RNA Interference
Alleles

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Genetic polymorphisms in the long noncoding RNA MIR2052HG offer a pharmacogenomic basis for the response of breast cancer patients to aromatase inhibitor therapy. / Ingle, James N.; Xie, Fang; Ellis, Matthew J.; Goss, Paul E.; Shepherd, Lois E.; Chapman, Judith Anne W; Chen, Bingshu E.; Kubo, Michiaki; Furukawa, Yoichi; Momozawa, Yukihide; Stearns, Vered; Pritchard, Kathleen I.; Barman, Poulami; Carlson, Erin E.; Goetz, Matthew P.; Weinshilboum, Richard M.; Kalari, Krishna R.; Wang, Liewei.

In: Cancer Research, Vol. 76, No. 23, 01.12.2016, p. 7012-7023.

Research output: Contribution to journalArticle

Ingle, JN, Xie, F, Ellis, MJ, Goss, PE, Shepherd, LE, Chapman, JAW, Chen, BE, Kubo, M, Furukawa, Y, Momozawa, Y, Stearns, V, Pritchard, KI, Barman, P, Carlson, EE, Goetz, MP, Weinshilboum, RM, Kalari, KR & Wang, L 2016, 'Genetic polymorphisms in the long noncoding RNA MIR2052HG offer a pharmacogenomic basis for the response of breast cancer patients to aromatase inhibitor therapy', Cancer Research, vol. 76, no. 23, pp. 7012-7023. https://doi.org/10.1158/0008-5472.CAN-16-1371
Ingle, James N. ; Xie, Fang ; Ellis, Matthew J. ; Goss, Paul E. ; Shepherd, Lois E. ; Chapman, Judith Anne W ; Chen, Bingshu E. ; Kubo, Michiaki ; Furukawa, Yoichi ; Momozawa, Yukihide ; Stearns, Vered ; Pritchard, Kathleen I. ; Barman, Poulami ; Carlson, Erin E. ; Goetz, Matthew P. ; Weinshilboum, Richard M. ; Kalari, Krishna R. ; Wang, Liewei. / Genetic polymorphisms in the long noncoding RNA MIR2052HG offer a pharmacogenomic basis for the response of breast cancer patients to aromatase inhibitor therapy. In: Cancer Research. 2016 ; Vol. 76, No. 23. pp. 7012-7023.
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AU - Xie, Fang

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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.

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AU - Kalari, Krishna R.

AU - Wang, Liewei

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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.

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