Oestrogens and Mammary Carcinogenesis

There is a large and compelling body of epidemiological and experimental evidence that oestrogens are the fuel behind the aetiology of breast cancer. The carcinogenic effects of oestrogen are postulated to be mediated by: the stimulation of cellular proliferation through their receptor-mediated hormonal activity. Other mechanisms include; direct genotoxic effects by increasing mutation rates through a cytochrome P450-mediated metabolic activation and induction of aneuploidy. The local biosynthesis of oestrogens, especially in postmenopausal women as a result of the interactions of various enzymes, is believed to play a very important role in the pathogenesis and development of hormone dependent breast carcinoma. The over-expression of such enzymes seems to be associated with the development of a more aggressive disease process, a poorer outcome and increased local and distant recurrences. This article focuses on CYP19 gene expression and aromatase enzyme activity and discusses their role in mammary carcinogenesis. The oestrogen producing enzymes such as 17-βhydroxysteroid dehydrogenase Type 1 (17-β-HSD), 2 and steroid sulphatase (STS), and their role in breast cancer development are also discussed in detail. In addition the role of oestrogen catalyzing enzymes including: 3-β-hydroxysteroid dehydrogenase, oestrogen sulfotransferase (EST), CYP1A1, CYP1B1, CYP3A4 and CYP3A5 are discussed. The understanding of the regulatory mechanisms controlling these enzymes is crucial to the development of new endocrine preventative and therapeutic strategies in post-menopausal females with hormone dependant breast cancer. Currently, the third generation of aromatase inhibitors has revolutionized the treatment of estrogen dependant breast cancer. However, the important role of both STS and 17-βHSD Type 1 in local estrogen production provides novel potential targets for endocrine therapy. Such endocrine therapy is currently being explored and the development of STS inhibitors, combined aromatase steroid sulfatase and 17β-HSD Type 1 inhibitors is underway, with promising preliminary results. Breast cancer affects around 1 in 10 women and is the leading cause of death in females between the ages of 40 and 50 years in the Western world (1). In the last decade, numerous studies have indicated a link between the pathogenesis of breast cancer and the expression of enzymes responsible for the local production of oestrogens. Oestrogen Metabolism The local production of oestrogens is mediated by a number of enzymes; aromatase catalyzes androstenedione into oestrone (E1), while steroid sulfatase (STS) hydrolyzes oestrone sulphate (E1S) to oestrone (Figure 1). Oestrone is subsequently converted to oestradiol (E2) by 17-βhydroxysteroid dehydro-genase Type 1 (17βHSD Type 1), and locally acts on breast cancer cells through oestrogen receptors. Additionally, other estrogen-metabolizing enzymes such as 3β-hydroxysteroid dehydrogenase, oestrogen sulfotransferase (STS), CYP1A1, CYP1B1, CYP3A4 and CYP3A5 play essential roles in the metabolism of oestrogen and subsequently in mammary carcinogenesis. Oestrogens and Mammary Carcinogenesis There is a large and compelling body of epidemiological and experimental evidence that oestrogens are the fuel behind the aetiology of breast cancer. Some breast carcinomas require oestrogen for continued growth and progression (2, 3). Three 1095 Correspondence to: Kefah Mokbel, The London Breast Institute, The Princess Grace Hospitals, 42-52 Nottingham Place, London, W1M 3FD, U.K. e-mail: [email protected]