The majority (75-80%) of breast cancers are hormone-sensitive and their growth is stimulated by the hormones estrogen and progesterone. In premenopausal women, most estrogen is produced by the ovaries, and selective estrogen receptor modulators such as tamoxifen are used to block the cancer-promoting properties of estrogen. In post-menopausal women, however, estrogens are produced largely by the action of aromatase on androgens produced by the adrenal glands, and reversible (anastrazole and letrazole) and irreversible (exemestane) inhibitors of aromatase have become widely used as treatments in these women. Now Dr Debashis Ghosh’s group at the Hauptman-Woodward Medical Research Institute have solved the structure of the aromatase cytochrome P450 enzyme from human placenta at 2.9Å resolution. The work is published in the 8 January 2009 issue of the journal Nature.
Unlike the active sites of many microsomal P450s that metabolise drugs and other xenobiotics, the aromatase, which is anchored in the membrane of the endoplasmic reticulum, has an androgen-specific cleft that forms hydrophobic and polar interactions with the substrate, androstenedione. The group hope that the new structural information will pave the way to improved aromatase inhibitors for the treatment of breast cancer. The group has previously solved the structures of two other enzymes involved in estrogen biosynthesis, estrone sulfatase (2003) and 17β-hydroxysteroid dehydrogenase type 1 (1996).