Stimulation of MCF-7 breast cancer cell proliferation by estrone sulfate and dehydroepiandrosterone sulfate: inhibition by novel non-steroidal steroid sulfatase inhibitors

Steroid sulfatase (STS) regulates the formation of active steroids from sys temic precursors, such as estrone sulfate and dehydroepiandrosterone sulfat e (DHEAS). In breast tissues, this pathway is a source for local production of estrogens, which support the growth of endocrine-dependent tumours. The refore, inhibitors of STS could have therapeutic potential. In this study, we report on substituted chromenone sulfamates as a novel class of non-ster oidal irreversible inhibitors of STS. The compounds are substantially more potent (6- to 80-fold) than previously described types of non-steroidal inh ibitors when tested against purified STS. In MCF-7 breast cancer cells, the y inhibit STS activity with IC50 below 100 pM. Importantly, the compounds a lso potently block estrone sulfate-stimulated growth of MCF-7 cells, again with IC50 below 100 pM. For one compound, we also observed a lack of any es trogenic effect at high concentrations (1 muM). We also demonstrate for the first time that STS inhibitors can block the DHEAS-stimulated growth of MC F-7 cells. Interestingly, this cannot be achieved with specific inhibitors of the aromatase, suggesting that stimulation of MCF-7 cell growth by DHEAS follows an aromatase-independent pathway. This gives further justification to consider steroid sulfatase inhibitors as potential drugs in the therapy of breast cancer. (C) 2000 Elsevier Science Ltd. All rights reserved.