Abstract
There is increasing evidence that recurrent metastatic breast cancer arises in part due to the presence of long-lived, slow-cycling, and drug-resistant stem cells. Adult stem cells, known as side population (SP) cells, whose phenotype has been demonstrated to be due to the expression of ABCG2, are known to be resistant to a number of structurally unrelated compounds. In the present study we have observed that while both oestrogen-responsive and non-oestrogen-responsive breast cancer cell lines contain SP, exhibit multidrug resistance and express elevated levels of ABCG2, the non-oestrogen-responsive more highly metastatic MDA-MB-231 SP cells exhibit higher levels of mitoxantrone resistance than the other cell populations examined. These SP cells would therefore have a higher survival capacity when exposed to many currently utilised therapeutic regimes. Importantly, we have shown there is a statistically significant relationship between the presence of these SP cells in fine needle aspirates associated with ER-negative palpable breast lesions, and that these cells are more frequently associated with triple-negative breast tumours. Novel treatments directed against SP cells should be sought to offer patients better treatment strategies in these triple-negative tumours that fail to respond to conventional targeted therapy. Further analysis of this small population of potentially important cells is warranted.
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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