Departments of Breast Medical Oncology (P.Y.M., B.A., P.F., D.M.Q.R., J.A.G., V.C.J.) and Computational Biology and Bioinformatics (B.M.B.), University of Texas, MD Anderson Cancer Center, Houston, Texas; King Faisal Specialist Hospital and Research (Gen.Org.), Research Center, Jeddah, Kingdom of Saudi Arabia (Y.M.H.); The Ben May Department for Cancer Research, University of Chicago, Chicago, Illinois (R.H., S.W.F., G.L.G.); Center for Precision Environmental Health and Department of Molecular and Cellular Biology (C.E.F.), Mass Spectrometry Proteomics Core (A.J., A.M.), Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Mass Spectrometry Proteomics Core (A.M.), and Dan L. Duncan Comprehensive Cancer Center (A.M., C.E.F.), Baylor College of Medicine, Houston, Texas; Adrienne Helis Malvin Medical Research Foundation, New Orleans, Louisiana (Y.C.); and Coriolan Dragulescu Institute of Chemistry, Romanian Academy, Timisoara, Romania (R.F.C.).
Departments of Breast Medical Oncology (P.Y.M., B.A., P.F., D.M.Q.R., J.A.G., V.C.J.) and Computational Biology and Bioinformatics (B.M.B.), University of Texas, MD Anderson Cancer Center, Houston, Texas; King Faisal Specialist Hospital and Research (Gen.Org.), Research Center, Jeddah, Kingdom of Saudi Arabia (Y.M.H.); The Ben May Department for Cancer Research, University of Chicago, Chicago, Illinois (R.H., S.W.F., G.L.G.); Center for Precision Environmental Health and Department of Molecular and Cellular Biology (C.E.F.), Mass Spectrometry Proteomics Core (A.J., A.M.), Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Mass Spectrometry Proteomics Core (A.M.), and Dan L. Duncan Comprehensive Cancer Center (A.M., C.E.F.), Baylor College of Medicine, Houston, Texas; Adrienne Helis Malvin Medical Research Foundation, New Orleans, Louisiana (Y.C.); and Coriolan Dragulescu Institute of Chemistry, Romanian Academy, Timisoara, Romania (R.F.C.)
Mol Pharmacol. 2020 Jul;98(1):24-37. doi: 10.1124/mol.120.119776. Epub 2020 May 3.
High-dose synthetic estrogen therapy was the standard treatment of advanced breast cancer for three decades until the discovery of tamoxifen. A range of substituted triphenylethylene synthetic estrogens and diethylstilbestrol were used. It is now known that low doses of estrogens can cause apoptosis in long-term estrogen deprived (LTED) breast cancer cells resistant to antiestrogens. This action of estrogen can explain the reduced breast cancer incidence in postmenopausal women over 60 who are taking conjugated equine estrogens and the beneficial effect of low-dose estrogen treatment of patients with acquired aromatase inhibitor resistance in clinical trials. To decipher the molecular mechanism of estrogens at the estrogen receptor (ER) complex by different types of estrogens-planar [17-estradiol (E)] and angular triphenylethylene (TPE) derivatives-we have synthesized a small series of compounds with either no substitutions on the TPE phenyl ring containing the antiestrogenic side chain of endoxifen or a free hydroxyl. In the first week of treatment with E the LTED cells undergo apoptosis completely. By contrast, the test TPE derivatives act as antiestrogens with a free para-hydroxyl on the phenyl ring that contains an antiestrogenic side chain in endoxifen. This inhibits early E-induced apoptosis if a free hydroxyl is present. No substitution at the site occupied by the antiestrogenic side chain of endoxifen results in early apoptosis similar to planar E The TPE compounds recruit coregulators to the ER differentially and predictably, leading to delayed apoptosis in these cells. SIGNIFICANCE STATEMENT: In this paper we investigate the role of the structure-function relationship of a panel of synthetic triphenylethylene (TPE) derivatives and a novel mechanism of estrogen-induced cell death in breast cancer, which is now clinically relevant. Our study indicates that these TPE derivatives, depending on the positioning of the hydroxyl groups, induce various conformations of the estrogen receptor's ligand-binding domain, which in turn produces differential recruitment of coregulators and subsequently different apoptotic effects on the antiestrogen-resistant breast cancer cells.
高剂量合成雌激素治疗是 30 年来治疗晚期乳腺癌的标准治疗方法，直到他莫昔芬的发现。使用了一系列取代的三苯乙烯合成雌激素和己烯雌酚。现在已知，低剂量的雌激素可以引起长期缺乏雌激素（LTED）的抗雌激素耐药乳腺癌细胞凋亡。这种雌激素的作用可以解释绝经后 60 岁以上服用结合马雌激素的女性乳腺癌发病率降低，以及临床试验中低剂量雌激素治疗获得性芳香酶抑制剂耐药患者的有益作用。为了解不同类型雌激素在雌激素受体（ER）复合物中的分子机制——平面[17-雌二醇（E）]和角型三苯乙烯（TPE）衍生物——我们合成了一系列化合物，这些化合物要么在含有他莫昔芬的反雌激素侧链的 TPE 苯环上没有取代基，要么含有游离羟基。在用 E 治疗的第一周，LTED 细胞完全凋亡。相比之下，测试的 TPE 衍生物作为抗雌激素，其苯环上含有他莫昔芬的反雌激素侧链的游离对羟基。如果存在游离羟基，则会抑制早期 E 诱导的凋亡。在他莫昔芬反雌激素侧链占据的位置没有取代基，导致与平面 E 相似的早期凋亡。TPE 化合物以可预测的方式将共调节剂募集到 ER 中，导致这些细胞的凋亡延迟。意义陈述：在本文中，我们研究了一系列合成三苯乙烯（TPE）衍生物的结构-功能关系以及雌激素诱导乳腺癌细胞死亡的新机制在临床上的相关性。我们的研究表明，这些 TPE 衍生物，取决于羟基的定位，诱导雌激素受体配体结合域的各种构象，进而导致共调节剂的不同募集，并随后对抗雌激素耐药乳腺癌细胞产生不同的凋亡作用。
