Abstract
Anterior Gradient-2 was identified using proteomic technologies as a protein overexpressed in human cancers. We show here properties of AG2 suggesting it has proto-oncogenic properties:(i) the AG2 protein and gene are unregulated in a tamoxifen resistance panel of breast cancer cells lines, (ii) cell lines overproducing AG2 have an elevated clonogenic activity in vitro and also increase cell growth in a xenograft model, (iii) AG2 protein inhibits the tumour suppressor protein p53, and (iv) AG2 localizes to the endoplasmic reticulum, suggesting a proto-onocogenic signalling pathway exists from endoplasmic reticulum to the nucleus to inhibit p53. To validate the AG2-mediated endoplasmic reticulum pathway as a possible drug target, we developed peptide aptamers to AG2 protein in order to determine whether the oncogenic properties of the protein can be altered by the peptide ligand. These studies hold promise for developing new types of drugs that can release and reactivate the tumour suppressor p53 in breast cancers.
Highlights
Ten to twenty per cent of breast tumours exhibit a basallike genetic profile and these tumours carry a poor prognosis
We have modelled the effects of polygenic predisposition in the East Anglian population, and have shown that the model predicts a wide distribution of individual risk in the population, such that half of all breast cancers may occur in the 12% of women at greatest risk
No single gene so far identified contributes more than 2% of the total inherited component, consistent with a model in which susceptibility is the result of a large number of individually small genetic effects
Summary
Ten to twenty per cent of breast tumours exhibit a basallike genetic profile and these tumours carry a poor prognosis. BRCA1 is a tumour suppressor gene which is mutated in up to 5–10% of breast cancer cases and is involved in multiple cellular processes including DNA damage control, cell cycle checkpoint control, apoptosis, ubiquitination and transcriptional regulation. Results We have previously carried out microarray-based expression profiling to examine differences in gene expression when BRCA1 is reconstituted in BRCA1 mutated HCC1937 breast cancer cells. We aim (i) to investigate the expression of the whole family of IAPs across a wide range breast cancer cell lines and tumour samples at both the RNA and protein level, and (ii) to determine whether targeting IAPs alters susceptibility to apoptosis. This study tested the hypothesis that Brk is involved in regulating the tumour cell environment during progression and investigated the effects of suppressing Brk in breast carcinoma cells to determine in which contexts Brk may be a valid therapeutic target. Molecular and clinical evidence points to a role for TGFβ signalling in cancer progression and metastasis; it is unclear at which points of the metastatic process TGFβ signalling occurs and whether it is necessary and/or sufficient to elicit cancer cell motility
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