Abstract
ERβ1 is often downregulated in cancer compared with normal cells, suggesting that it may function as a tumour suppressor and could play an important role in carcinogenesis. The expression of ERβ1 is regulated by multiple mechanisms such as methylation. Five splice variants of ERβ mRNA have been identified, ERβ1 to ERβ5. However, it is unclear whether and how the full-length version, ERβ1, is regulated post-transcriptionally. MicroRNAs are a class of nonprotein coding small RNAs that regulate expression of genes at post-transcriptional levels. Using rapid amplification of 3' complementary DNA ends (3'RACE), we have confirmed 3' untranslated region (3'UTR) expression and sequences of ERβ1 mRNA in MCF-7 cells. Based on miRNA expression profiling of human breast cancer studies, we found that miR-92 is upregulated in malignant breast. In silico analysis using the miRGen database and RNA hybrid predicted that there are two putative miR-92 target sequences within the 3'UTR of human ERβ1 mRNA. Firstly, we profiled the expression of ERβ1 mRNA and miR-92 in breast cancer tissue and cell lines. miR-92 levels were higher in ERβ1-negative MDA-MB-453 cells than ERβ1-positive MCF-7 cells. We observed miR-92 upregulation in breast tumours while ERβ1 mRNA expression was decreased compared with matched adjacent normal tissues. We found a significant negative correlation between miR-92 and ERβ1 mRNA and protein in breast tumour (r = -0.5, P = 0.001 and r = -0.39, P = 0.037), respectively. Transfection of MCF-7 cells with anti-miR-92 increased endogenous ERβ1 mRNA and reduced cell proliferation. EGFP report experiment also confirms that the 3'UTR of ERβ1 carries the directly binding sites of miR-92. Finally, we showed that miR-92 expression is modulated by the ER ligands 17β-estradiol and tamoxifen in MCF-7 cells. These findings prove that ERβ1 expression is negatively regulated at a post-transcriptional level by miR-92. This miRNA could be considered a potential therapeutic target in breast cancer.
Highlights
The response rarely sustains long among the responders for Herceptin monotherapy treatment
We have provided a novel mechanism of acquired resistance to Herceptin in human epidermal growth factor receptor 2 (HER2)-positive breast cancer and have resolved the inconsistencies in the literature regarding the effect of Herceptin on HER2 phosphorylation
Using a range of biochemical and cell-biology techniques, we have shown that BRCA1 is modified by SUMO in response to genotoxic stress, and co-localises at sites of DNA damage with SUMO1, SUMO2/3 and the SUMO conjugating enzyme Ubc9
Summary
The response rarely sustains long among the responders for Herceptin (trastuzumab) monotherapy treatment. BRCA1 is strongly implicated in the maintenance of genomic stability by its involvement in multiple cellular pathways including DNA damage signalling, DNA repair, cell cycle regulation, protein ubiquitination, chromatin remodelling, transcriptional regulation and apoptosis Both pathological and gene expression profiling studies provide evidence that breast cancers with germline mutations in BRCA1 are different from non-BRCA1-related breast cancers. The vitreous humour is one of the few tissues in the body that is avascular and virtually acellular, and previous studies have indicated that opticin contributes to the maintenance of this state by inhibition of angiogenesis The aim of this present study is to investigate the effect and mode of action of opticin in suppressing tumour cell proliferation and migration in vitro in a panel of breast cancer cell lines and to establish its therapeutic efficacy in human breast tumour xenografts in vivo. Using receptorselective ligands (patent filed by MRC Technology) specific for the TRAIL death receptors, TRAIL-R1/TRAIL-R2, we have previously shown that primary leukaemic cells isolated from patients with chronic lymphocytic leukaemia can be selectively sensitized to apoptosis by combining an a histone deacetylase inhibitor (HDACi) with a TRAIL-R1-specific form of TRAIL/TRAIL-R1 mAb
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