Inhibition of aldo-keto reductase (AKR1C3) activity and function in breast cancer

Abstract

The aldo-keto reductase enzyme AKR1C3 has been implicated to be involved in estrogen receptor-positive breast cancer in postmenopausal women. It reduces weak estrone to potent 17β-estradiol in the breast, which promotes the activation of the estrogen receptor, leading to downstream signalling and increased cell proliferation. AKR1C3 also functions as a prostaglandin synthase converting prostaglandin D2 to 11β-prostagladin F2α, which can also stimulate cell proliferation via F-prostanoid receptor activation. Novel selective inhibitors of AKR1C3 were used to evaluate the activity and function of AKR1C3 in ER-positive breast cancer and to determine whether AKR1C3 inhibitors are an effective therapeutic strategy for ER-positive breast cancer. Biological activity was determined in a panel of cell lines expressing variable levels of AKR1C3. The formation of 11β-prostaglandin F2α and 17β-estradiol after stimulation of exogenous substrates for AKR1C3 were used to determine AKR1C3 activity, while AKR1C3 function was assessed by cell proliferation. Results showed that AKR1C3 had a major role on the production of 11β-prostaglandin F2α from PGD2, but inhibiting this activity had only a minor effect on cell proliferation. Conversely, AKR1C3 had only a minor role on 17β-estradiol production from estrone, with other enzymes including 17β- hydroxysteroid dehydrogenase type 1 also involved, but this resulted in a significant reduction in estrone-stimulated cell proliferation in AKR1C3 expressing estrogendependent breast cancer cell lines. The results suggest AKR1C3 inhibitors are not an effective therapeutic strategy for the whole population of ER-positive breast cancer patients, but they could potentially be useful in patients that express high AKR1C3 or low levels of other 17β-estradiol producing enzymes and are given in combination with other agents that target estrogen signalling.