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an early menopause is protective; these data suggest that breast cancer risk is related to a cumulative exposure to ovarian hormones. Oestrogen (E) is the focus of breast cancer therapies because tumours are often dependent on this steroid for growth
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School of Medicine and Medical Science, Endocrine Oncology Research Group, UCD Conway Institute, St Vincent's University Hospital and University College Dublin, Dublin 4, Ireland
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School of Medicine and Medical Science, Endocrine Oncology Research Group, UCD Conway Institute, St Vincent's University Hospital and University College Dublin, Dublin 4, Ireland
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School of Medicine and Medical Science, Endocrine Oncology Research Group, UCD Conway Institute, St Vincent's University Hospital and University College Dublin, Dublin 4, Ireland
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treated with oestrogen therapy for gynaecological conditions, but not for postmenopausal patients treated with low-dose oestrogen replacement therapy. Recently, it has been shown that among parous women of reproductive age, a recent pregnancy is associated
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Introduction The most widely used and best-studied antihormonal approach in clinical breast cancer is the antioestrogen tamoxifen ( Johnston et al. 2003 ). Tamoxifen competitively inhibits binding of oestrogen to its target
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Introduction
The past four years have seen an explosion of interest and concern with respect to ‘environmental hormone disruptors’, particularly environmental oestrogens. This is a consequence of (i) the discovery that a range of widely- used man-made chemicals (including certain pesticides, alkyphenols, phthalate esters and phenolic compounds), to which we are exposed daily, can act as weak oestrogens, and (ii) their hypothetical links to an increase in disorders of reproductive development and function in the human male and in some species of wildlife (Toppari et al. 1996). Additionally, several other ubiquitous chemicals to which man has had considerable exposure over the past half-century are potent anti-androgens (notably the fungicide vinclozolin (Kelce et al. 1994) and the principle, and most persistent, metabolite of DDT in the body, p,p-DDE (Kelce et al. 1995)). These discoveries have prompted numerous television programmes, government-funded enquiries and reports and have even led to legislative changes in the USA. Inevitably, speculation and exaggerated claims have appeared in the popular press, these have generally not been based on solid scientific foundation (see Kavlock et al. 1996, Ashby et al. 1997). On the other hand, the coincidence is striking between human exposure to these man-made chemicals and the apparent increase in prevalence of a range of hormone-dependent human cancers of reproductive tissues (breast, prostate, endometrium, testis and ovary). We therefore need to know whether these chemicals are directly involved in the aetiology of any of these cancers, so that human exposure to such chemicals can be reduced. Unfortunately, as this review will demonstrate, obtaining the data which would enable unequivocal, informed risk assessment is anything but straightforward (Kavlock et al. 1996, Ashby et al. 1997).
Acknowledgements
We are appreciative of the extreme tolerance of the Editor, Professor Vivian James, throughout the passing of many missed deadlines for submission of this review.
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. One such candidate compound is the oestrogen metabolite 2-methoxyoestradiol (2ME), which is now in clinical trials for the treatment of various cancers ( Mooberry 2003 ). 2ME is produced by sequential hepatic hydroxylation and methylation from the
Deeley Research Centre, Department of Biochemistry and Microbiology, Department of Biochemistry and Medical Genetics, Department of Pathology and Laboratory Medicine, BC Cancer Agency, 2410 Lee Avenue, 3rd Floor Research, Victoria, British Columbia, Canada V8R 6V5
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Deeley Research Centre, Department of Biochemistry and Microbiology, Department of Biochemistry and Medical Genetics, Department of Pathology and Laboratory Medicine, BC Cancer Agency, 2410 Lee Avenue, 3rd Floor Research, Victoria, British Columbia, Canada V8R 6V5
Deeley Research Centre, Department of Biochemistry and Microbiology, Department of Biochemistry and Medical Genetics, Department of Pathology and Laboratory Medicine, BC Cancer Agency, 2410 Lee Avenue, 3rd Floor Research, Victoria, British Columbia, Canada V8R 6V5
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Introduction Oestrogen receptor alpha (ERα) is a central factor in breast cell biology and growth. As the primary transcription factor that mediates oestrogen signalling, ER is the linchpin of endocrine therapy and a feature that partly defines the
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Abstract
Breast cancer remains a major cause of death in postmenopausal women. Concentrations of the biologically active oestrogen, oestradiol, are increased in breast tumours and there is now good evidence that cytokines which are present in tumours can stimulate tumour oestrogen synthesis. In this study we have examined the ability of interleukin-6 (IL-6) or tumour necrosis factor α (TNFα), either alone or in combination, to stimulate aromatase, oestradiol dehydrogenase (reductive) or oestrone sulphatase activities in cultured breast cancer cells. Both IL-6 and TNFα were able to stimulate the activities of these enzymes but in combination acted synergistically to markedly enhance enzyme activity. The possibility that α2-macroglobulin might also interact with IL-6 to enhance oestradiol dehydrogenase activity was also examined but no evidence for any synergistic interaction between these two factors was obtained. Cytokines, such as IL-6 and TNFα, are emerging as having a central role in regulating breast tumour oestrogen synthesis. Understanding the role that cytokines have in regulating oestrogen synthesis in breast tumours should lead to the development of novel therapeutic agents for use in the treatment of women with breast cancer.
Endocrine-Related Cancer (1997) 4 323-330
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randomized trial comparing upfront surgery versus neo-adjuvant chemotherapy ( Vergote 2008 ) has demonstrated similar survival in the two arms, but reduced morbidity in primary chemotherapy. In the present study, we assessed oestrogen receptor (ESR
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