Estrone sulfate stimulates growth of nitrosomethylurea-induced breast carcinoma in vivo in the rat.

Concentrations of estradiol in human breast tumors from pre- and post-menopausal women are similar whereas plasma levels are 5- to 60-fold lower in post-menopausal women. The mechanism for maintaining high tumor tissue estrogen levels in post-menopausal women is unknown but could be related to the ability of plasma estrone sulfate to serve as a precursor for estradiol synthesis in tumor tissue. Estrone sulfate plasma levels are 30-fold higher than free estradiol levels in post-menopausal women and estrone sulfatase is present in many tissues, including breast tumors, supporting this hypothesis. In this study, we examined the ability of exogenously administered estrone sulfate to stimulate growth of a carcinogen-induced, hormone-dependent rat mammary tumor and measured the rate of conversion of estrone sulfate to free estrone and estradiol. Castrate rats bearing nitrosomethylurea-induced mammary tumors were infused with estradiol as a control or estrone sulfate over a 14-day period. Estradiol at low doses significantly increased tumor volume whereas higher amounts paradoxically inhibited growth. By comparison, estrone sulfate infusions significantly increased tumor volume over that observed in castrate animals on both days 7 and 14 of infusion. To determine whether estrone sulfate was converted to free estrone and estradiol during this protocol, 3H-estrone sulfate was substituted for unlabelled steroid and castrate animals were again infused for 14 days. At 7, 10 and 14 days of infusion, 18-26% of estrone sulfate was converted to free estrone and 9-16% to free estradiol. There were no significant differences between the 2 doses used and the rates of conversion were stable over the infusion period. Conversion of estrone sulfate to free estradiol was also demonstrated by radioimmunoassay of free estradiol in plasma during estrone sulfate infusions. These data demonstrate that exogenously administered estrone sulfate can stimulate mammary tumor growth in castrate animals and support the possibility that estrone sulfate may serve as an important source of tumor tissue estradiol.