Determinants of tissue oestradiol levels in human breast cancer

A variety of clinical and experimental evidence indicates that the oestrogens are the major hormones affecting human breast cancer growth. The goal of recent treatment strategies is to reduce the amount of oestradiol acting locally on the tumour. For this reason, it is relevant to examine what determines tumour tissue oestradiol concentrations. Various steps are potentially important and include glandular or extraglandular production of oestradiol, tissue uptake, binding to receptors and the rate of local tissue oestradiol synthesis. In premenopausal women, glandular secretion of oestradiol by the ovary provides the major source of tissue oestradiol. In postmenopausal women, the extraglandular conversion of androstenedione to oestrone and then oestradiol in peripheral tissues accounts for 90% of circulating oestradiol. However, plasma levels of oestradiol in postmenopausal women are only 4 to 40% of those found in premenopausal patients and yet breast cancer tissue levels are similar. This observation suggests the possibility of local oestradiol synthesis by breast tumours in postmenopausal women. We examined two pathways which could be involved in local oestradiol synthesis: the androstenedione to oestrone (aromatase) pathway and the oestrone-sulphate to oestrone (sulphatase) system. Seventy-nine of 128 tumours contained aromatase with activity ranging from 5-80 pmol/g protein/hr. This enzyme was of high affinity with a Km of 0.027 microM. Sulphatase, on the other hand, was present in all tumours with activity ranging from 0.8-125 microM. Its affinity was appreciably lower with a Km of 27 microM. Comparing both activities at substrate concentrations approaching physiological levels, we detected 10-fold higher activity with sulphatase than with aromatase. Further studies revealed the presence of 17 beta-hydroxysteroid dehydrogenase in all tumors studied. Whereas 50% of tissues contained both a high and a low affinity type of activity, the remainder had only the low activity form. Since our data favoured the oestrone-sulphate to oestrone to oestradiol pathway as biologically relevant, we sought to determine whether oestrone-sulphate could act as an oestrogen after conversion to oestradiol. Using an NMU rat mammary tumour soft agar colony forming assay, we found that oestrone-sulphate stimulated colony growth in a manner consistent with its 1% conversion to oestradiol by cells in the agar dishes. Furthermore, preliminary data indicate that oestrone-sulphate can stimulate NMU tumour growth in vivo in rats. The metabolism of oestradiol in tissue can also determine its biological effects and its tissue levels.(ABSTRACT TRUNCATED AT 400 WORDS)