Novel SOAT inhibitors block DHEAS transport and suppress proliferation in MCF-7 breast cancer cells

Abstract

Intracrine estrogen formation from adrenal precursors such as dehydroepiandrosterone sulfate (DHEAS) plays a critical role in sustaining estrogen receptor (ER)-positive breast cancer cell proliferation, particularly in postmenopausal women. The sodium-dependent organic anion transporter (SOAT, gene symbol SLC10A6) facilitates the cellular uptake of sulfated steroids, thereby making these precursors available for local estrogen biosynthesis. However, the impact of SOAT inhibition on intracrine estrogen metabolism in breast cancer remains unclear. We investigated the effects of pharmacological SOAT inhibition on SOAT-mediated DHEAS transport, cell proliferation and intracrine estradiol synthesis in SOAT-overexpressing MCF-7 breast cancer cells (MCF-7_SOAT). These MCF-7_SOAT cells were treated with the SOAT inhibitor S1647, as well as two newly synthesized derivatives (compounds 12 and 24) that exhibit enhanced selectivity and potency. DHEAS uptake and downstream steroid metabolism were quantified using LC–MS/MS, while DHEAS-induced cell proliferation was analyzed using [³H]thymidine incorporation. SOAT inhibition markedly reduced sodium-dependent DHEAS uptake, resulting in decreased intracellular estradiol synthesis and suppression of estrogen-dependent proliferation without cytotoxicity. These findings confirm that SOAT is a critical upstream regulator of intracrine estrogen biosynthesis in breast cancer cells and highlight compounds 12 and 24 as promising candidates for further preclinical development aimed at reducing local estrogen production.