Steroid metabolism in breast cancer.
The endocrine system and its steroids have long been thought to be instrumental in the etiology of breast cancer. A large proportion of cancerous breast tissues have been shown to express estrogen (ER), androgen (AR) and progesterone (PR) receptors. It is through these receptors that steroid hormones can exert their mitogenic effects. The local biosynthesis of estrogens is believed to play an integral part in the development of hormone-dependent breast cancer and recent studies on the use of inhibitors to block this steroid production has yielded an improvement of prognosis in breast cancer patients. Consequently, the understanding of the enzymes involved in the synthesis and metabolism of estrogens in breast cancer is paramount to treating this malignancy. This review examines the biological and clinical relevance of three key endocrine enzymes: steroid sulfatase (STS), aromatase (Arom), and 17beta-hydroxysteroid dehydrogenase (17beta-HSD) type-1. The importance of the over expression and increased activity of these enzymes in breast tissue and on breast cancer is discussed. Importantly, the intratumoral biosynthesis of estrogens is examined in detail. The effects of new inhibitors of these enzymes on the growth of hormone-dependent breast cancer will also be investigated. First and second generation STS inhibitors and third generation aromatase inhibitors are showing significant promise, whereas inhibitors for 17beta-HSD type-1 are still at an early stage. However, such endocrine therapy that is currently being explored has shown promising results for patients with hormone-dependent breast cancer.
Foster
P A
PA
Endocrinology and Metabolic Medicine and Sterix Ltd., Faculty of Medicine, Imperial College London, St Mary's Hospital, London, W2 1NY, UK. paul.foster@imperial.ac.uk
D015067:17-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000728:Androgens / Q000378:metabolism; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use; D001141:Aromatase / Q000378:metabolism*; D047072:Aromatase Inhibitors / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D004960:Estradiol Dehydrogenases; D004967:Estrogens / Q000378:metabolism; D005260:Female; D006801:Humans; D008593:Menopause; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy / Q000378:metabolism; D011374:Progesterone / Q000378:metabolism; D013256:Steroids / Q000378:metabolism*; D043266:Steryl-Sulfatase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
D000728:Androgens; D018931:Antineoplastic Agents, Hormonal; D047072:Aromatase Inhibitors; D004967:Estrogens; D009363:Neoplasm Proteins; D013256:Steroids; D011374:Progesterone; D015067:17-Hydroxysteroid Dehydrogenases; D004960:Estradiol Dehydrogenases; C523763:HSD17B2 protein, human; D001141:Aromatase; D043266:Steryl-Sulfatase