title: Post-transcriptional regulation of human breast cancer cell proteome by unliganded estrogen receptor β via microRNAs.
abstract: Estrogen receptor β (ERβ) is a member of the nuclear receptor family of homeostatic regulators that is frequently lost in breast cancer (BC), where its presence correlates with a better prognosis and a less aggressive clinical outcome of the disease. In contrast to ERα, its closest homolog, ERβ shows significant estrogen-independent activities, including the ability to inhibit cell cycle progression and regulate gene transcription in the absence of the ligand. Investigating the nature and extent of this constitutive activity of ERβ in BC MCF-7 and ZR-75.1 cells by means of microRNA (miRNA) sequencing, we identified 30 miRNAs differentially expressed in ERβ+ versus ERβ- cells in the absence of ligand, including up-regulated oncosuppressor miRs such miR-30a. In addition, a significant fraction of >1,600 unique proteins identified in MCF-7 cells by iTRAQ quantitative proteomics were either increased or decreased by ERβ, revealing regulation of multiple cell pathways by ligand-free receptors. Transcriptome analysis showed that for a large number of proteins regulated by ERβ, the corresponding mRNAs are unaffected, including a large number of putative targets of ERβ-regulated miRNAs, indicating a central role of miRNAs in mediating BC cell proteome regulation by ERβ. Expression of a mimic of miR-30a-5p, a direct target and downstream effector of ERβ in BC, led to the identification of several target transcripts of this miRNA, including 11 encoding proteins whose intracellular concentration was significantly affected by unliganded receptor. These results demonstrate a significant effect of ligand-free ERβ on BC cell functions via modulation of the cell proteome and suggest that miRNA regulation might represent a key event in the control of the biological and clinical phenotype of hormone-responsive BC by this nuclear receptor.
authors: Laboratory of Molecular Medicine and Genomics, Department of Medicine and Surgery, University of Salerno, 84081 Baronissi (SA), Italy;
authors: Giovanni
authors: G
authors: Nassa
authors: Roberta
authors: R
authors: Tarallo
authors: Giorgio
authors: G
authors: Giurato
authors: Maria Rosaria
authors: MR
authors: De Filippo
authors: Maria
authors: M
authors: Ravo
authors: Francesca
authors: F
authors: Rizzo
authors: Claudia
authors: C
authors: Stellato
authors: Concetta
authors: C
authors: Ambrosino
authors: Marc
authors: M
authors: Baumann
authors: Niina
authors: N
authors: Lietzèn
authors: Tuula A
authors: TA
authors: Nyman
authors: Alessandro
authors: A
authors: Weisz
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000235:genetics / Q000378:metabolism*; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D061986:MCF-7 Cells; D035683:MicroRNAs / Q000235:genetics*; D040901:Proteomics; D017423:Sequence Analysis, RNA
chemical_list: D047629:Estrogen Receptor beta; D004967:Estrogens; D035683:MicroRNAs