Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA.
Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA.
Breast Cancer Res Treat. 2020 Jun;181(2):297-307. doi: 10.1007/s10549-020-05629-y. Epub 2020 Apr 10.
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.
MCF7 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.
许多人类乳腺癌对内分泌治疗产生耐药性并复发，这是由于雌激素受体 (ERα) 突变导致其具有组成型活性和更具侵袭性的表型。在这里，我们研究了一种新型金刚烷类抗雌激素药物 K-07 抑制含有两种最常见 ER 激活突变（Y537S 和 D538G）的乳腺癌转移生长以及在临床前转移性癌症模型中延长生存的效果。
将表达荧光素酶和 Y537S 或 D538G ER 的 MCF7 乳腺癌细胞注入 NOD-SCID-gamma 雌性小鼠体内，并通过口服给予抗雌激素 K-07 或对照载体进行治疗。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，并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特征分析。
这些乳腺癌细胞在肝和肺中建立了转移，K-07 治疗减少了转移负担。接受 K-07 治疗的小鼠也存活得更长。到第 70 天，只有 28%的携带突变 ER 转移的载体处理小鼠存活，而所有 K-07 处理的 D538G 和 Y537S 小鼠仍存活。K-07 还显著降低了转移性细胞 ER 的水平和 ER 调节基因的表达。
抗雌激素 K-07 可以减少体内乳腺癌的转移，并在这个由组成型激活的突变 ER 驱动的临床前模型中延长宿主的生存，这表明该化合物可能适合进一步研究其在抑制含有组成型激活的突变 ER 的乳腺癌转移中的疗效。
