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.