Abstract
Previous data have shown that FOXM1 expression is elevated in breast cancer tissues and is strongly correlated with the expression pattern of ERα in breast cancer cells. The expression of ERα is a good prognostic factor in breast cancer, as about two-thirds of these ERα-positive patients respond to treatment with antiestrogens. However, approximately one-half of the patients that initially respond to hormonal therapy develop resistance. Since FOXM1 is critical for the progression of the cell cycle, we investigated the regulation of FOXM1 by ERα and its role in endocrine sensitivity and resistance in breast cancer cells. We firstly observed by quantitative RT-PCR a strong and significant positive correlation between ERα and FOXM1 mRNA expression in breast cancer patient samples. We showed that FOXM1 protein and mRNA expression was regulated by ER ligands. We also demonstrated that ectopic conditional expression of ERα, in the presence of estrogens, leads to induction of FOXM1 expression in ER-negative U2OS cells. Using reporter gene assays, we demonstrated that ERα activates FOXM1 transcription through an estrogen-response element site. The direct binding of ERα to the FOXM1 promoter was confirmed in vitro by mobility shift and DNA pull-down assays and in vivo by chromatin immunoprecipitation analysis. Importantly, silencing of FOXM1 by RNA interference abolishes the estrogen-mediated MCF-7 cell proliferation. Conversely, ectopic expression of a constitutively active FOXM1 can abrogate the cell cycle arrest mediated by the antiestrogen tamoxifen. Taken together, the results clearly demonstrate FOXM1 as a key mediator of the mitogenic functions of ERα and estrogen in breast cancer cells. Our findings that antiestrogens repress FOXM1 expression in endocrine-sensitive but not endocrine-resistant breast carcinoma cell lines and that ectopic expression of an active FOXM1 can abrogate the anti-proliferative effects of tamoxifen also suggest that deregulation of FOXM1 may also contribute to antiestrogen insensitivity.
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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