Oestrogen producing enzymes and mammary carcinogenesis: a review.
There is a large and compelling body of epidemiological and experimental evidence that oestrogens are instrumental in the aetiology of breast cancer. Their mechanisms of action are varied, including stimulation of cellular proliferation through receptor-mediated hormonal activity, increasing genetic mutation rates through cytochrome P450-mediated metabolic activation, and induction of aneuploidy. The local biosynthesis of oestrogens especially in postmenopausal women is believed to play a very important role in the pathogenesis and development of hormone dependent breast carcinoma and the over-expression of regulatory enzymes seems to be associated with the development of a more aggressive disease and associated with poor outcome and increased local and distant recurrences. In this article we highlight the role of CYP19 gene expression and aromatase activity in mammary carcinogenesis. Other oestrogen producing (17-beta-hydroxysteroid dehydrogenase and steroid sulphatase) and catalyzing enzymes (3-beta-hydroxysteroid dehydrogenase, Oestrogen sulfotransferase, CYP1A1, CYP1B1, and CYP3A4) are also discussed in some detail. Understanding the mechanisms that regulate these enzymes is crucial to the development of new endocrine therapies in post-menopausal females with hormone dependant breast cancer. Currently, third generation aromatase inhibitors has revolutionized the treatment of oestrogen dependant breast cancer. However, the important role of both STS and 17-beta-HSD type 1 in local oestrogen 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 inhibitors and 17-beta-HSD type 1 inhibitors is underway with promising initial results.
Subramanian
Ashok
A
St. George's Hospital, Blackshaw Road, Tooting, London, UK.
Salhab
Mohamed
M
Mokbel
Kefah
K
D015067:17-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D000818:Animals; D001141:Aromatase / Q000235:genetics / Q000502:physiology*; D047072:Aromatase Inhibitors / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000209:etiology*; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D004967:Estrogens / Q000096:biosynthesis*; D006801:Humans; D043266:Steryl-Sulfatase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*
D047072:Aromatase Inhibitors; D004791:Enzyme Inhibitors; D004967:Estrogens; D015067:17-Hydroxysteroid Dehydrogenases; D001141:Aromatase; D043266:Steryl-Sulfatase