Reductive 17β-hydroxysteroid
dehydrogenases (17β-HSDs) and 11β-hydroxysteroid
dehydrogenase 2 (11β-HSD2) play crucial roles in respectively regulating
steroids and
glucocorticoids for the progression of
hormone-dependent
breast cancer. Most studies focused on the function and individual regulation of these
enzymes. However, mutual regulation of these
enzymes and the induced modulation on the
estrogen and
androgen receptors for
breast cancer promotion are not yet clear. In this study, MCF-7 and T47D cells were treated with inhibitors of 17β-HSD1, 17β-HSD7,
aromatase or
steroid sulfatase (STS), then
mRNA levels of 17β-HSD7, STS, 11β-HSD 2,
estrogen receptors α (ERα) and
androgen receptor (AR) were determined by Q-PCR. ER negative cell line MDA-MB-231 was used as a negative control. Our results demonstrate that 17β-HSD7, STS and 11β-HSD2 are all regulated by the same
estrogen estradiol via ERα. When the gene of ERα (ESR1) was knocked down, there was no longer significant mutual regulation of these
enzymes. Our results demonstrate that important steroidogenic
enzymes transcriptionally regulated by ERα, can be mutually closely correlated. Inhibition of one of them can reduce the expression of another, thereby amplifying the role of the inhibition. Furthermore, inhibition of 17β-HSD7 increases the expression of AR gene which is considered as a marker for better prognosis in ER + breast
cancer, while maintaining ERα level. Thus, our mechanistic finding provides a base for further improving the endocrine
therapy of ER + breast
cancer, e.g., for selecting the target
steroid enzymes, and for the combined targeting of human 17β-HSD7 and ERα.