A new approach to the prevention of breast cancer

Abstract

SynopsisWhile the role of oestrogens in breast cancer has been recognised for over a century, until recently our understanding of the mechanism by which they act has been limited, despite zealous efforts on the part of many investigators to seek for differences in oestrogen levels or metabolism in cancer patients. Since the initiation of breast cancer occurs many years before the detection of overt disease, it seems reasonable to suggest that these earlier studies may have been carried out at the wrong stage of the disease. Using a time invariant radiometric procedure, we have established that of the three principal sites of oestrogen metabolism at C-2, C-16α, and C-17, only C-16α hydroxylation is elevated in women with breast cancer. Further studies in women at high risk for breast cancer for familial reasons showed that they have an elevated rate of 16α-hydroxylation. Parallel studies in mice with high and low rates of spontaneous mammary tumour formation show a close parallelism between the extent of 16α-hydroxylation and tumour incidence. Studies of 16α-hydroxyoestrone, the product of 16α-hydroxylation, have demonstrated that it is a unique oestrogen, capable of binding irreversibly to the oestrogen receptor and permanently activating it. Studies on the effects of diet and drugs on the extent of C-2 and C-16α hydroxylation have shown that while the former reaction is easily increased or decreased, the latter is refractory to treatment and behaves like a constitutive enzyme. Thus, treatment with cimetidine, obesity, or high fat diets decrease the extent of C-2 hydroxylation, while high protein diets, hyperthyroidism, smoking, or dioxins increase C-2 hydroxylation. In contrast, 16α-hydroxylation is essentially unchanged in any of these conditions.A link between increased C-2 hydroxylation and decreased levels of breast and endometrial cancer is suggested by epidemiological studies in smokers. Conversely, decreases in this reaction as in obesity are associated with increased risk for these tumours. The aim of these studies is to develop a safe prophylactic regimen which will increase C-2 hydroxylation, resulting in a decrease in active oestrogen and a lower tumour incidence.