Wang Xiaoqiang, Gérard Catherine, Thériault Jean-François, Poirier Donald, Doillon Charles J, Lin Sheng-Xiang
Laboratory of Molecular Endocrinology and Oncology, Centre Hospitalier Universitaire de Québec Research Center (CHUL, CHU) and Laval University, Québec City, Québec, G1V4G2, Canada.
Laboratory of Molecular Endocrinology and Oncology, Centre Hospitalier Universitaire de Québec Research Center (CHUL, CHU) and Laval University, Québec City, Québec, G1V4G2, Canada
J Mol Cell Biol. 2015 Dec;7(6):568-79. doi: 10.1093/jmcb/mjv028. Epub 2015 May 12.
17β-hydroxysteroid dehydrogenase (17β-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 17β-HSD type 7 (17β-HSD7), which activates estrone while markedly inactivating DHT. The role of DHT in breast cancer cell proliferation is 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 17β-HSD7 in breast carcinoma. Inhibition of 17β-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 G(0)/G(1) 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 17β-HSD7 expression. Decreased plasma E2 and elevated plasma DHT levels were also found. Thus, the dual functional 17β-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.
17β-羟基类固醇脱氢酶1型（17β-HSD1）被认为是阻断雌激素依赖性乳腺癌中雌激素生成最后一步的关键靶点。最近双氢睾酮（DHT）在对抗雌激素诱导的细胞生长中作用的确认促使我们研究还原型17β-羟基类固醇脱氢酶7型（17β-HSD7），它可激活雌酮，同时显著使DHT失活。DHT在乳腺癌细胞增殖中的作用通过其在生理浓度雌二醇（E2）存在下对细胞生长的独立抑制得以证明。此外，对Oncomine数据集中大量临床样本的综合分析表明17β-HSD7在乳腺癌中过表达。抑制乳腺癌细胞中的17β-HSD7会导致E2水平降低和DHT水平升高，继而诱导细胞周期蛋白D1、p21、Bcl-2和Bik的调控，从而使细胞周期停滞在G(0)/G(1)期，并引发细胞凋亡以及该酶的自身下调反馈。这种抑制导致异种移植肿瘤显著缩小，癌细胞密度降低，17β-HSD7表达减少。还发现血浆E2降低和血浆DHT水平升高。因此，通过调节E2和DHT的平衡，双功能的17β-HSD7被提议作为雌激素依赖性乳腺癌的新靶点。这表明在普遍认为该酶主要作用于胆固醇代谢的观念上有了概念性的进展。
