Abstract
Studies have shown that cancer stem-like cells (CSCs) from solid cancers are resistant to both radiotherapy and chemotherapy. We have shown that primary breast cancers (n = 8) and a breast cancer cell line (MCF7) enriched for breast cancer stem cells (BCSC) using mammosphere (MS) clonogenic culture can preferentially survive radiotherapy and chemotherapy treatment in vitro, showing ≥ 50% increase in MS survival compared with non-BCSC enriched cells. The BCSC enriched population, defined by the cell surface markers ESA+/CD44+/CD24-/low, had reduced levels of DNA damage (measured by γH2AX) after 4 Gy irradiation or doxorubicin (1 μM) treatment. This suggests that the BCSC enriched population avoids or repairs the DNA damage significantly more than the whole population. Differentiating agents have been used to re-sensitise breast cancers to endocrine treatment but effects on BCSC are unknown. All-trans-retinoic acid (ATRA), tricostatin A and vorinostat caused a dose-dependent decrease in the BCSC population using MS culture and FACS analysis after 72 hours of treatment in a monolayer. Vorinostat (100 nM) showed the greatest effect, with 80% reduction in the ESA+/CD44+/CD24-/low population and a 50% reduction in MS formation. Our data suggest that in vitro treatment with differentiating agents reduces the number of the BCSC within the MCF7 cell line. Combination of ATRA (2 μM) or vorinostat with 6 Gy irradiation caused a significant reduction in MS survival showing a 30% and 70% decrease compared with an irradiated control. Similarly, in combination with paclitaxel (0.5 μM) ATRA and vorinostat caused a significant reduction in MS survival, showing 70% and 60% decrease compared with paclitaxel alone. In primary breast cancers (n = 3), combination of ATRA and 6 Gy irradiation significantly decreased MS formation by ≥ 25% respectively compared with irradiation alone. These observations suggest that targeting BCSC with agents that eliminate or differentiate BCSC is a promising strategy to overcome resistance to radiotherapy and chemotherapy in the clinic.
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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