title: MicroRNA-135b regulates ERα, AR and HIF1AN and affects breast and prostate cancer cell growth.
abstract: MicroRNAs (miRNAs) regulate a wide range of cellular signaling pathways and biological processes in both physiological and pathological states such as cancer. We have previously identified miR-135b as a direct regulator of androgen receptor (AR) protein level in prostate cancer (PCa). We wanted to further explore the relationship of miR-135b to hormonal receptors, particularly estrogen receptor α (ERα). Here we show that miR-135b expression is lower in ERα-positive breast tumors as compared to ERα-negative samples in two independent breast cancer (BCa) patient cohorts (101 and 1302 samples). Additionally, the miR-135b expression is higher in AR-low PCa patient samples (47 samples). We identify ERα as a novel miR-135b target by demonstrating miR-135b binding to the 3'UTR of the ERα and decreased ERα protein and mRNA level upon miR-135b overexpression in BCa cells. MiR-135b reduces proliferation of ERα-positive BCa cells MCF-7 and BT-474 as well as AR-positive PCa cells LNCaP and 22Rv1 when grown in 2D. To identify other genes regulated by miR-135b we performed gene expression studies and found a link to the hypoxia inducible factor 1α (HIF1α) pathway. We show that miR-135b influences the protein level of the inhibitor for hypoxia inducible factor 1α (HIF1AN) and is able to bind to HIF1AN 3'UTR. Our study demonstrates that miR-135b regulates ERα, AR and HIF1AN protein levels through interaction with their 3'UTR regions, and proliferation in ERα-positive BCa and AR-positive PCa cells.
authors.affiliation: Institute for Molecular Medicine Finland, FIMM, Helsinki, Finland; VTT Technical Research Centre of Finland, Medical Biotechnology, Turku, Finland; Turku Centre for Biotechnology, University of Turku, Turku, Finland. Electronic address: anna.aakula@fimm.fi.
authors.forename: Anna
authors.initials: A
authors.lastname: Aakula
authors.affiliation: Department of Genetics, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway; The K.G. Jebsen Center for Breast Cancer Research, Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
authors.forename: Suvi-Katri
authors.initials: SK
authors.lastname: Leivonen
authors.affiliation: Institute for Molecular Medicine Finland, FIMM, Helsinki, Finland.
authors.forename: Petteri
authors.initials: P
authors.lastname: Hintsanen
authors.affiliation: Institute for Molecular Medicine Finland, FIMM, Helsinki, Finland.
authors.forename: Tero
authors.initials: T
authors.lastname: Aittokallio
authors.affiliation: Department of Laboratory Medicine, Division of Translational Cancer Research, Lund University, Lund, Sweden.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Ceder
authors.affiliation: Department of Genetics, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway; The K.G. Jebsen Center for Breast Cancer Research, Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
authors.forename: Anne-Lise
authors.initials: AL
authors.lastname: Børresen-Dale
authors.affiliation: VTT Technical Research Centre of Finland, Medical Biotechnology, Turku, Finland.
authors.forename: Merja
authors.initials: M
authors.lastname: Perälä
authors.affiliation: Institute for Molecular Medicine Finland, FIMM, Helsinki, Finland.
authors.forename: Päivi
authors.initials: P
authors.lastname: Östling
authors.affiliation: Institute for Molecular Medicine Finland, FIMM, Helsinki, Finland.
authors.forename: Olli
authors.initials: O
authors.lastname: Kallioniemi
mesh_terms: D020413:3' Untranslated Regions; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation / Q000502:physiology*; D015536:Down-Regulation; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000502:physiology*; D006899:Mixed Function Oxygenases / Q000235:genetics / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D020413:3' Untranslated Regions; D047628:Estrogen Receptor alpha; C544965:MIRN135 microRNA, human; D035683:MicroRNAs; D011944:Receptors, Androgen; D012097:Repressor Proteins; D006899:Mixed Function Oxygenases; C439790:HIF1AN protein, human
keywords: Androgen receptor (AR); Breast cancer (BCa); Estrogen receptor α (ERα); Hypoxia inducible factor 1 alpha subunit inhibitor (HIF1AN); MicroRNA (miRNA); Prostate cancer (PCa)