Post-transcriptional regulation of human breast cancer cell proteome by unliganded estrogen receptor ? via microRNAs.

ABSTRACT: Estrogen receptor ? (ER?) 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 ER?, its closest homolog, ER? 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 ER? in BC MCF-7 and ZR-75.1 cells by means of microRNA (miRNA) sequencing, we identified 30 miRNAs differentially expressed in ER?+ versus ER?- 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 ER?, revealing regulation of multiple cell pathways by ligand-free receptors. Transcriptome analysis showed that for a large number of proteins regulated by ER?, the corresponding mRNAs are unaffected, including a large number of putative targets of ER?-regulated miRNAs, indicating a central role of miRNAs in mediating BC cell proteome regulation by ER?. Expression of a mimic of miR-30a-5p, a direct target and downstream effector of ER? 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 ER? 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.

SUBMITTER: Nassa G 

PROVIDER: S-EPMC3977185 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature