The regulation of oestrogen biosynthesis in human adipose tissue

Abstract

SynopsisThe enzyme complex responsible for the conversion of androgens to oestrogens is called aromatase. This enzyme is expressed in a number of tissue sites, including granulosa cells, placenta, hypothalamus and adipose. Oestrogen formation in adipose tissue has been implicated in the aetiology of endometrial and breast cancer. Aromatase comprises two components: a member of the cytochrome P-450 gene family known as aromatase cytochrome P-450, and a flavoprotein, NADPH-cytochrome P-450 reductase. We have recently obtained a full-length cDNA insert encoding human aromatase cytochrome P-450 and have expressed it in COSI monkey kidney tumour cells. The resulting transcript encodes a protein which is capable of converting androstenedione, testosterone and 16α-hydroxyandrostenedione to the corresponding oestrogens. Furthermore, characterisation of the aromatase cytochrome P-450 gene indicates that in humans there is only one such gene, which spans about 30kb and has at least nine exons. From these results we conclude that there is only one aromatase enzyme in humans. Study of the expression of this enzyme in human adipose stromal cells indicates that it is subject to regulation by a number of factors including cAMP, phorbol esters, and the growth factors, EGF, TGF-α, TGF-β, TNF and 1Lβ. Since several of these growth factors are produced by breast cancer cells in response to oestrogens, the possibility exists for paracrine and autocrine feedback loops within the breast, in which the growth of a tumour is regulated by oestrogen produced locally in the adipose cells of the surrounding tissue, and this in turn is regulated by the growth factors produced by the tumour as a result of oestrogen action.