Abstract
Melanoma-associated antigen (MAGE) family genes are broadly expressed during development and are involved in the regulation of cell survival, cell cycle progression and apoptosis. MAGE family proteins are generally described as tumour-specific antigens and as representing ideal targets for cancer immunotherapy. In the current study, we identified melanoma-associated antigen protein-D4 (MAGE-D4), a recently characterised MAGE family member, as a new prognostic biomarker and potential therapeutic target for breast cancer. Specifically, in a whole genome microarray analysis of 103 cases of invasive breast tumours, MAGE-D4 expression was observed in 43.8% of tumours, while undetectable in normal breast tissue. Multivariate and univariate analyses also indicated MAGE-D4 expression to be associated with tumour grade, spread to lymph nodes and shortened times to relapse (P = 0.0369) and death (P = 0.0133) from time of cancer diagnosis; suggesting a role for MAGE-D4 in tumour progression. To further investigate the involvement of MAGE-D4 in breast cancer cell biology, the phenotypic effects of this gene were characterised in vitro. We observed a marked upregulation of MAGE-D4 expression - at both mRNA and protein levels - in the breast cancer cell line Hs578T compared with the syngenic Hs578Bst breast cell line. Interestingly, RNA interference-mediated knockdown of MAGE-D4 expression in Hs578T cells significantly reduced cell migration and invasion and correlated with inhibition of STAT3 and NF-κB p65 subunit phosphorylation, thus affecting two common signalling pathways involved in regulating cancer progression. Moreover, monolayer cell growth rate was not affected by MAGE-D4 gene knockdown, while growth in soft agar was significant compromised. Our results indicate that MAGE-D4 contributes to the tumorigenesis of breast cancer cells by regulating migration, invasion and anchorage-independent growth, and therefore may represent a novel target for the detection and treatment of 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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