Inhibition of tumor necrosis factor alpha-stimulated aromatase activity by microtubule-stabilizing agents, paclitaxel and 2-methoxyestradiol.
The aromatase enzyme, which converts androstenedione to oestrone, regulates the availability of oestrogen to support the growth of hormone-dependent breast tumours. Cytokines, such as interleukin 6 (IL-6) and tumour necrosis factor alpha (TNFalpha) or prostaglandin E(2) (PGE(2)), can stimulate aromatase activity. These factors may originate from cells of the immune system that infiltrate breast tumours. Paclitaxel, which is used in the treatment of breast cancer, stabilizes microtubules and has previously been shown to rapidly down-regulate TNF-receptors on human macrophages. The endogenous oestrogen metabolite, 2-methoxyestradiol (2-meOE2), also acts to stabilize microtubules. In this study, we have examined the ability of paclitaxel or 2-meOE2 to antagonise TNFalpha-stimulated aromatase activity in stromal fibroblasts derived from normal or malignant breast tissues. Paclitaxel inhibited basal and TNFalpha-stimulated aromatase activities by 88% and 91% respectively. 2-MeOE2 also reduced basal and TNFalpha-stimulated aromatase activities by 46% and 56% respectively. Both paclitaxel and 2-meOE2 also inhibited stimulation of aromatase activity by IL-6 plus its soluble receptor and PGE(2). The 16alpha-hydroxylated derivative of 2-meoE2 and 2-meOE3, which does not bind to microtubules, was less effective at inhibiting TNFalpha-stimulated aromatase activity. Increased 2-hydroxylation of oestrogens, and subsequent formation of their 2-methoxy derivatives, may be associated with a reduced risk of breast cancer. It is possible that the pathway of oestrogen metabolism may influence the ability of stromal cells to respond to cytokine stimulation.
Purohit
A
A
Imperial College School of Medicine, St Mary's Hospital, London, W2, 1NY, United Kingdom.
Singh
A
A
Ghilchik
M W
MW
Reed
M J
MJ
D000077584:2-Methoxyestradiol; D001141:Aromatase / Q000378:metabolism; D047072:Aromatase Inhibitors; D001940:Breast / Q000166:cytology; D002478:Cells, Cultured; D015232:Dinoprostone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology; D008870:Microtubules / Q000187:drug effects* / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology*; D019947:Receptors, Interleukin-6 / Q000502:physiology; D012995:Solubility; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D047072:Aromatase Inhibitors; D015850:Interleukin-6; D019947:Receptors, Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D004958:Estradiol; D000077584:2-Methoxyestradiol; D001141:Aromatase; D015232:Dinoprostone; D017239:Paclitaxel