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 language | English |
|---|---|
| Pages (from-to) | 7012-7023 |
| Number of pages | 12 |
| Journal | Cancer Research |
| Volume | 76 |
| Issue number | 23 |
| DOIs | |
| Publication status | Published - 01-12-2016 |
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All Science Journal Classification (ASJC) codes
- Oncology
- Cancer Research
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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 journal › Article
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
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
VL - 76
SP - 7012
EP - 7023
JO - Cancer Research
JF - Cancer Research
SN - 0008-5472
IS - 23
ER -