Suppression of breast cancer metastasis and extension of survival by a new antiestrogen in a preclinical model driven by mutant estrogen receptors.
Suppression of breast cancer metastasis and extension of survival by a new antiestrogen in a preclinical model driven by mutant estrogen receptors.
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DOI：
10.1007/s10549-020-05629-y
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发表时间：
2020-06
影响因子：
3.8
通讯作者：
Katzenellenbogen BS
中科院分区：
文献类型：
--
作者：
Laws MJ;Ziegler Y;Shahoei SH;Dey P;Kim SH;Yasuda M;Park BH;Nettles KW;Katzenellenbogen JA;Nelson ER;Katzenellenbogen BS
许多人乳腺肿瘤对内分泌治疗产生耐药性，并由于雌激素受体（ERα）突变而复发，这些突变传递了组成性活性和更具侵袭性的表型。在这里，我们研究了一种新的金刚烷基抗雌激素，K-07，在抑制乳腺癌转移的生长含有两个最常见的ER激活突变，Y 537 S和D538 G，并在延长生存期的临床前转移癌模型的有效性。将表达荧光素酶和Y 537 S或D538 G ER的MCF-7乳腺癌细胞注射到NOD-SCID-γ雌性小鼠中，并用抗雌激素K-07或对照载体口服处理动物。还与抗雌激素氟维司群进行了比较。通过体内生物发光成像监测转移的发展，通过免疫组织化学和生化分析对肝和肺中的转移进行表型表征。这些乳腺癌细胞在肝和肺中建立了转移，K-07治疗降低了转移负荷。用K-07处理的小鼠也存活了更长时间。到第70天，只有28%的具有突变型ER转移的溶媒处理的小鼠存活，而所有K-07处理的D538 G和Y 537 S小鼠仍然存活。K-07还显著降低转移细胞ER水平和ER调节基因的表达。抗雌激素K-07可以减少乳腺癌的体内转移，并延长由组成型活性突变ER驱动的临床前模型中的宿主存活期，这表明该化合物可能适合于进一步翻译检查其在抑制含有组成型活性突变ER的乳腺癌转移中的功效。
Many human breast tumors become resistant to endocrine therapies and recur due to estrogen receptor (ERα) mutations that convey constitutive activity and a more aggressive phenotype. Here, we examined the effectiveness of a novel adamantyl antiestrogen, K-07, in suppressing the growth of breast cancer metastases containing the two most frequent ER-activating mutations, Y537S and D538G, and in extending survival in a preclinical metastatic cancer model. MCF-7 breast cancer cells expressing luciferase and Y537S or D538G ER were injected into NOD-SCID-gamma female mice, and animals were treated orally with the antiestrogen K-07 or control vehicle. Comparisons were also made with the antiestrogen Fulvestrant. The development of metastases was monitored by in vivo bioluminescence imaging with phenotypic characterization of the metastases in liver and lung by immunohistochemical and biochemical analyses. These breast cancer cells established metastases in liver and lung, and K-07 treatment reduced the metastatic burden. Mice treated with K-07 also survived much longer. By day 70, only 28% of vehicle-treated mice with mutant ER metastases were alive, whereas all K-07-treated D538G and Y537S mice were still alive. K-07 also markedly reduced the level of metastatic cell ER and the expression of ER-regulated genes. The antiestrogen K-07 can reduce in vivo metastasis of breast cancers and extend host survival in this preclinical model driven by constitutively active mutant ERs, suggesting that this compound may be suitable for further translational examination of its efficacy in suppression of metastasis in breast cancers containing constitutively active mutant ERs.
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影响因子：
4
作者：
Ratajczak MZ;Jadczyk T;Schneider G;Kakar SS;Kucia M
通讯作者：
Kucia M
影响因子：
8.8
作者：
Lopez-Knowles, Elena;Pearson, Alex;Dowsett, Mitch
通讯作者：
Dowsett, Mitch
DOI：
10.1158/1078-0432.ccr-13-2332
发表时间：
2014-04-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Jeselsohn R;Yelensky R;Buchwalter G;Frampton G;Meric-Bernstam F;Gonzalez-Angulo AM;Ferrer-Lozano J;Perez-Fidalgo JA;Cristofanilli M;Gómez H;Arteaga CL;Giltnane J;Balko JM;Cronin MT;Jarosz M;Sun J;Hawryluk M;Lipson D;Otto G;Ross JS;Dvir A;Soussan-Gutman L;Wolf I;Rubinek T;Gilmore L;Schnitt S;Come SE;Pusztai L;Stephens P;Brown M;Miller VA
通讯作者：
Miller VA
影响因子：
8.8
作者：
Li S;Shen D;Shao J;Crowder R;Liu W;Prat A;He X;Liu S;Hoog J;Lu C;Ding L;Griffith OL;Miller C;Larson D;Fulton RS;Harrison M;Mooney T;McMichael JF;Luo J;Tao Y;Goncalves R;Schlosberg C;Hiken JF;Saied L;Sanchez C;Giuntoli T;Bumb C;Cooper C;Kitchens RT;Lin A;Phommaly C;Davies SR;Zhang J;Kavuri MS;McEachern D;Dong YY;Ma C;Pluard T;Naughton M;Bose R;Suresh R;McDowell R;Michel L;Aft R;Gillanders W;DeSchryver K;Wilson RK;Wang S;Mills GB;Gonzalez-Angulo A;Edwards JR;Maher C;Perou CM;Mardis ER;Ellis MJ
通讯作者：
Ellis MJ
影响因子：
10.3
作者：
Marshall, Jean-Claude A.;Collins, Joshua W.;Steeg, Patricia S.
通讯作者：
Steeg, Patricia S.