title: Genetic Polymorphisms in the Long Noncoding RNA MIR2052HG Offer a Pharmacogenomic Basis for the Response of Breast Cancer Patients to Aromatase Inhibitor Therapy.
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. Cancer Res; 76(23); 7012-23. ©2016 AACR.
authors.affiliation: Division of Medical Oncology, Mayo Clinic, Rochester, Minnesota. ingle.james@mayo.edu.
authors.forename: James N
authors.initials: JN
authors.lastname: Ingle
authors.affiliation: Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota.
authors.forename: Fang
authors.initials: F
authors.lastname: Xie
authors.affiliation: Baylor Breast Center, Houston, Texas.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Ellis
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard University, Boston, Massachusetts.
authors.forename: Paul E
authors.initials: PE
authors.lastname: Goss
authors.affiliation: Canadian Cancer Trials Group, Kingston, Ontario, Canada.
authors.forename: Lois E
authors.initials: LE
authors.lastname: Shepherd
authors.affiliation: Canadian Cancer Trials Group, Kingston, Ontario, Canada.
authors.forename: Judith-Anne W
authors.initials: JW
authors.lastname: Chapman
authors.affiliation: Canadian Cancer Trials Group, Kingston, Ontario, Canada.
authors.forename: Bingshu E
authors.initials: BE
authors.lastname: Chen
authors.affiliation: RIKEN Center for Integrative Medical Science, Yokohama, Japan.
authors.forename: Michiaki
authors.initials: M
authors.lastname: Kubo
authors.affiliation: University of Tokyo, Tokyo, Japan.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Furukawa
authors.affiliation: RIKEN Center for Integrative Medical Science, Yokohama, Japan.
authors.forename: Yukihide
authors.initials: Y
authors.lastname: Momozawa
authors.affiliation: Johns Hopkins School of Medicine, Baltimore, Maryland.
authors.forename: Vered
authors.initials: V
authors.lastname: Stearns
authors.affiliation: Sunnybrook Odette Regional Cancer Centre, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Kathleen I
authors.initials: KI
authors.lastname: Pritchard
authors.affiliation: Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota.
authors.forename: Poulami
authors.initials: P
authors.lastname: Barman
authors.affiliation: Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota.
authors.forename: Erin E
authors.initials: EE
authors.lastname: Carlson
authors.affiliation: Division of Medical Oncology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Goetz
authors.affiliation: Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Weinshilboum
authors.affiliation: Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota.
authors.forename: Krishna R
authors.initials: KR
authors.lastname: Kalari
authors.affiliation: Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota.
authors.forename: Liewei
authors.initials: L
authors.lastname: Wang
mesh_terms: D047072:Aromatase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics*; D045744:Cell Line, Tumor; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D008875:Middle Aged; D011110:Polymorphism, Genetic; D062085:RNA, Long Noncoding / Q000235:genetics*
chemical_list: D047072:Aromatase Inhibitors; D062085:RNA, Long Noncoding