Abstract
Mammary cancer can develop for many reasons; one is the exposure to environmental carcinogens and/or steroid hormones. The cytochrome P450 enzyme family catalyses not only the metabolism of a wide range of carcinogens but is also involved in the metabolism of steroids. This process alters their steroidogenic properties, a mechanism important for mammary carcinogenesis. At the centre of this research are cytochrome P450 1B1 (CYP1B1) and cytochrome P450 1A1 (CYP1A1). Unlike many other P450s, these isoforms are expressed extrahepatically. CYP1B1 protein is found to be overexpressed in tumours compared with the corresponding healthy tissues. Special regulatory mechanisms are likely to cause this difference. In this study we employed TaqMan analysis, immunoblotting and reporter assays to investigate the expression patterns of CYP1B1 and CYP1A1 in a panel of breast cancer cell lines derived from different stages of mammary carcinomas. Furthermore, we investigated the expression of these P450s in cell lines derived from primary human mammary epithelial cells (HMECs) that have been transfected with various combinations of oncogenes and telomerase. In the transformed HMECs we found that the expression of CYP1B1, CYP1A1 and their inducibility by TCDD was differentially affected by the different oncogenes. We are presently investigating the regulatory mechanisms that cause this response. In a second investigation, we analysed the relevance of P450 expression for mammary-tumour development and tumour therapy. For this purpose we have developed MCF-7-derived cell lines in which the expression of CYP1A1 and CYP1B1 can be switched on by treatment with low doses of doxycycline. We demonstrated that expression of these P450s altered the effects of estrogens and antiestrogens on cell cycle and apoptotic markers. Currently, the MCF-7-derived cell lines are being grown in xenografts. P450 expression will be induced by doxicycline in the drinking water, and animals will be treated with or without tamoxifen. Subsequently, the effects of P450 expression on tumour growth, angiogenesis and apoptosis will be measured. It is anticipated that the results of these investigations will greatly enhance our understanding about the aetiology of breast cancer and may provide strategies to improve treatment.
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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