title: Tamoxifen differentially regulates miR-29b-1 and miR-29a expression depending on endocrine-sensitivity in breast cancer cells.
abstract: Endocrine-resistance develops in ∼40% of breast cancer patients after tamoxifen (TAM) therapy. Although microRNAs are dysregulated in breast cancer, their contribution to endocrine-resistance is not yet understood. Previous microarray analysis identified miR-29a and miR-29b-1 as repressed by TAM in MCF-7 endocrine-sensitive breast cancer cells but stimulated by TAM in LY2 endocrine-resistant breast cancer cells. Here we examined the mechanism for the differential regulation of these miRs by TAM in MCF-7 versus TAM-resistant LY2 and LCC9 breast cancer cells and the functional role of these microRNAs in these cells. Knockdown studies revealed that ERα is responsible for TAM regulation of miR-29b-1/a transcription. We also demonstrated that transient overexpression of miR-29b-1/a decreased MCF-7, LCC9, and LY2 proliferation and inhibited LY2 cell migration and colony formation but did not sensitize LCC9 or LY2 cells to TAM. Furthermore, TAM reduced DICER1 mRNA and protein in LY2 cells, a known target of miR-29. Supporting this observation, anti-miR-29b-1 or anti-miR-29a inhibited the suppression of DICER by 4-OHT. These results suggest miR-29b-1/a has tumor suppressor activity in TAM-resistant cells and does not appear to play a role in mediating TAM resistance.
authors.affiliation: Department of Biochemistry & Molecular Genetics, Center for Genetics and Molecular Medicine, University of Louisville School of Medicine, Louisville, KY 40292, USA.
authors.forename: Penn
authors.initials: P
authors.lastname: Muluhngwi
authors.affiliation: Department of Biochemistry & Molecular Genetics, Center for Genetics and Molecular Medicine, University of Louisville School of Medicine, Louisville, KY 40292, USA.
authors.forename: Abirami
authors.initials: A
authors.lastname: Krishna
authors.affiliation: Department of Biochemistry & Molecular Genetics, Center for Genetics and Molecular Medicine, University of Louisville School of Medicine, Louisville, KY 40292, USA.
authors.forename: Stephany L
authors.initials: SL
authors.lastname: Vittitow
authors.affiliation: Department of Biochemistry & Molecular Genetics, Center for Genetics and Molecular Medicine, University of Louisville School of Medicine, Louisville, KY 40292, USA.
authors.forename: Joshua T
authors.initials: JT
authors.lastname: Napier
authors.affiliation: Department of Biochemistry & Molecular Genetics, Center for Genetics and Molecular Medicine, University of Louisville School of Medicine, Louisville, KY 40292, USA.
authors.forename: Kirsten M
authors.initials: KM
authors.lastname: Richardson
authors.affiliation: Department of Biochemistry & Molecular Genetics, Center for Genetics and Molecular Medicine, University of Louisville School of Medicine, Louisville, KY 40292, USA.
authors.forename: Mackenzie
authors.initials: M
authors.lastname: Ellis
authors.affiliation: Department of Biochemistry & Molecular Genetics, Center for Genetics and Molecular Medicine, University of Louisville School of Medicine, Louisville, KY 40292, USA.
authors.forename: Justin L
authors.initials: JL
authors.lastname: Mott
authors.affiliation: Department of Biochemistry & Molecular Genetics, Center for Genetics and Molecular Medicine, University of Louisville School of Medicine, Louisville, KY 40292, USA. Electronic address: carolyn.klinge@louisville.edu.
authors.forename: Carolyn M
authors.initials: CM
authors.lastname: Klinge
mesh_terms: D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D049109:Cell Proliferation; D004965:Estrogen Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D013629:Tamoxifen / Q000494:pharmacology / Q000627:therapeutic use*; D014162:Transfection
chemical_list: D004965:Estrogen Antagonists; D035683:MicroRNAs; D013629:Tamoxifen
keywords: Breast cancer; Endocrine-resistance; Estrogen receptor; Tamoxifen; miRNA-29a; miRNA-29b-1