Reductive 17beta-hydroxysteroid dehydrogenases in the sulfatase pathway: critical in the cell proliferation of breast cancer.

Estradiol, the most potent estrogen, plays critical roles in tumor cell proliferation and breast cancer development. It can be synthesized via the aromatase pathway or the sulfatase pathway, and the later has been demonstrated to be more significant. Reductive 17beta-hydroxysteroid dehydrogenases (17beta-HSDs) catalyze the last step in estrogen activation and are thus critical in breast cancer development. 17beta-HSD Type 1 (17beta-HSD1) is of great importance since it efficiently synthesizes the most potent estrogen estradiol, as well as other estrogens as 5-androstene-3beta,17beta-diol and 5alpha-androstane-3beta,17beta-diol, and inactivates the most active androgen dihydrotestosterone (DHT), all contributing to the stimulation and development of breast cancers. Rational inhibitor design based on the new structure information has been developed, yielding interesting compounds and lead chemicals. This was demonstrated by a hybrid inhibitor that interacts with both the substrate and cofactor binding sites and a recently designed inhibitor 3-(3',17'beta-dihydroxyestra-1',3',5'(10')-trien-16'beta-methyl) benzamide which has been crystallized in complex with 17beta-HSD1. Both inhibitors demonstrate nM level K(i)in vitro. New non-steroidal inhibitors have been designed and reported very recently. The Type 7 17beta-HSD, expressed in several tissues including breast and ovary, can also contribute to estrogen synthesis and DHT inactivation in breast cancer cells. The enzyme role in steroid metabolism and cancer cell proliferation needs to be compared to that in cholesterogenesis. Breast cancer cell lines provide an excellent platform for such study. T47D, MCF-7 and MDA-MB-231-luc cells have been used to create xenografts in nude mice as animal models, now with the possibility of bioluminescent imaging to provide rapid, non-invasive, and quantitative analysis of tumor biomass and metastasis. Here we review the roles of the sulfatase and aromatase pathways and the contribution of the reductive 17beta-HSDs for hormone metabolism in breast cancer.