Personne :
Doillon, Charles

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Centre Hospitalier de l'Université Laval (CHUL), Faculté de médecine, Université Laval
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  • Publication
    Synergistic control of sex hormones by 17b-HSD type 7 : a novel target for estrogen-dependent breast cancer
    (Oxford University Press, 2015-05-12) Poirier, Donald; Wang, Xiao Qiang; Gérard, Catherine; Lin, Sheng-Xiang; Doillon, Charles; Thériault, Jean-François
    17b-hydroxysteroid dehydrogenase (17b-HSD) type 1 is known as a critical target to block the final step of estrogen production in estrogen-dependent breast cancer. Recent confirmation of the role of dyhydroxytestosterone (DHT) in counteracting estrogen induced cell growth prompted us to study the reductive 17b-HSD type 7 (17b-HSD7), which activates estrone while markedly inactivating DHT. The role of DHTin breast cancer cell proliferationis demonstrated by its independent suppression of cell growth in the presence of a physiological concentration of estradiol (E2). Moreover, an integral analysis of a large number of clinical samples in Oncomine datasets demonstrated the overexpression of 17b-HSD7 in breast carcinoma. Inhibition of 17b-HSD7 in breast cancer cells resulted in a lower level of E2 and a higher level of DHT, successively induced regulation of cyclinD1, p21, Bcl-2, and Bik, consequently arrested cell cycle in the G0/G1 phase, and triggered apoptosis and auto-downregulation feedback of the enzyme. Such inhibition led to significant shrinkage of xenograft tumors with decreased cancer cell density and reduced 17b-HSD7 expression. Decreased plasma E2 and elevated plasma DHT levels were also found. Thus, the dual functional 17b-HSD7 is proposed as a novel target for estrogen-dependent breast cancer by regulating the balance of E2 and DHT. This demonstrates a conceptual advance on the general belief that the major role of this enzyme is in cholesterol metabolism.