Hormone replacement therapy and cancers: the biological roles of estrogen and progestin in tumorigenesis are different between the endometrium and breast.

Hormone replacement therapy (HRT) has become available over the past few decades, but the risk of breast cancer with HRT remains controversial. The Women's Health Initiative Study has recently demonstrated that women receiving estrogen plus progestin (HRT) have an increased risk of invasive breast carcinoma, although women receiving estrogen alone (estrogen replacement therapy) exhibit no increased risk of breast carcinoma. By contrast, the risk of endometrial carcinoma increases with estrogen replacement therapy, while HRT reduces the risk of endometrial carcinoma. These clinical findings suggest that the biological roles of estrogen and progestin in tumorigenesis are certainly different between the endometrium and breast, although both are considered "estrogen-dependent tissues". In this review, I summarize the recent studies and indicate that the enzymes responsible for intratumoral estrogen metabolism and biosynthesis are markedly different between human breast and endometrial carcinomas. 17beta-hydroxysteroid dehydrogenases (17-HSDs) are enzymes estrogen replacement therapyinvolved in the formation of active sex steroids. Estrogens are interconverted by two enzymes, 17-HSD types 1 and 2. Type 1 converts estrone to estradiol, and type 2 catalyzes the reverse reaction. 17-HSD type 5 reduces androstenedione to testosterone. 17-HSD type 1 plays an important role in the regulation of high estradiol levels in breast carcinoma tissues, whereas 17-HSD types 2 and 5 appear to be essential for the maintenance of estradiol concentrations in endometrial carcinoma tissues. In addition, the biological significance of progesterone receptor isoforms differs between endometrial and breast carcinomas. These findings may provide new insights into the biology of "estrogen-dependent tissues".