Aromatase and the breast: regulation and clinical aspects

The aromatase enzyme is unique to the pathway of oestrogen biosynthesis and converts androgen precursors into oestrogens, major stimulatory factors for breast cancer proliferation. Although there is only a single gene for aromatase and a single protein for the enzyme, transcriptional control is complex using different promoters which are in part tissue-specific. These generate different mRNA transcripts that vary in the presence/absence of individual untranslated exon 1s. In breast cancers, species vary between individual tumours, types I.3 and I.4 being the major species in some tumours but type II predominates in the majority. Since the type II promoter is regulated by prostaglandins/cyclic AMP, agents signalling through these systems seem largely responsible for local regulation of intratumoural oestrogen biosynthesis. Autocrine production of these factors would account for the high activity in breast cancers and paracrine secretion for the raised activity in breast fat associated with the local presence of cancer. Given the central role of oestrogen in normal development and pathological processes, there has been great interest in controlling aromatase activity by the use of specific inhibitors. Clinically, this is particularly evident in the management of postmenopausal women with breast cancer.