A hypothesis implicating adrenal dehydroepiandrosterone (DHEA) (sulfate) in the etiology of human breast cancer of the “adrenal” or “Western” type has been presented (Adams, J. B. Steroid Hormones and Human Breast Cancer. An Hypothesis. Cancer, 40: 325–333, 1977). High concentrations of DHEA sulfate in the blood provide a potentially high flux of the free steroid to mammary tumors, due to the presence therein of a sulfatase. The free steroid, in turn, is metabolized by human mammary tumors in vitro to 5-androstene-3β,17β-diol (ADIOL) and 7-hydroxydehydroeplandrosterone. It has now been found that ADIOL when administered s.c. to immature female rats will deplete the estrogen receptor in the uterine cytosol. Similarly, dimethylbenzanthracene-induced rat mammary tumors, when incubated in vitro with 1 µm ADIOL, show translocation of the estrogen receptor from cytosol to the nucleus, as measured by exchange assays. The magnitude of depletion of cytosol estrogen receptor by ADIOL was less than that obtained with 17β-estradiol, studied at 0.03 µm concentrations, but greater than that with 1 µm dihydrotestosterone. Among a wide group of C19 steroids examined as possible inhibitors of estrogen sulfotransferase, both DHEA and ADIOL showed marked inhibitory properties. By contrast, both 7α- and 7β-hydroxydehydroepiandrosterone showed negligible inhibitory effects. This paralleled previous findings on the influence of a 7-hydroxyl group in modifying the ability of ADIOL to compete effectively for the estrogen receptor. Thus the high levels of 7-hydroxylase found in human mammary tumors, and acting on both DHEA and ADIOL, may function in controlling the intracellular concentrations of these steroids.

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Presented at the John E. Fogarty International Center Conference on Hormones and Cancer, March 29 to 31, 1978, Bethesda, Md. Supported by grants from the Australian National Health and Medical Research Council.

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