the mTOR translational control pathway in tamoxifen resistant ER+ breast cancer

项目摘要。雌激素受体阳性(ER+)乳腺癌占大多数(~70%-80%) 乳腺癌，大多数晚期复发源于惰性或潜伏期乳腺癌，以及 大多数乳腺癌死亡是由转移性疾病引起的。三苯氧胺的抗内分泌治疗 仍然是ER+乳腺癌辅助治疗的基石，特别是在绝经前的妇女中， 而且在绝经后环境中用芳香酶抑制剂治疗之后也是如此。然而，许多人 在最初的治疗中，女性对他莫昔芬没有反应，而在有反应的人中，三分之一会因耐药而复发 以及15年内的转移性疾病。因此，内分泌耐药的ER+乳腺癌仍然是 乳腺癌转移和死亡的主要原因。事实上，对他莫昔芬的初始或获得性耐药性是 在所有ER+乳腺癌死亡中，有一半以上与此有关。逆转他莫昔芬治疗的耐药性是一种 关键的首要乳腺癌挑战。 我们提供临床前研究，证明发现了提供他莫昔芬的关键轴 表皮生长因子受体(EGFR)/雌激素介导的ER+乳腺癌细胞耐药 受体α(ER-α)途径及其对选择性翻译的影响。 此外，我们还证明，有几种针对其他适应症的实验性药物可以 被重新用于靶向这一轴治疗对他莫昔芬耐药的ER+乳腺癌。他莫昔芬是一种 雌激素受体拮抗小分子药物在全球范围内用于治疗ER+乳腺癌。 耐药性通常与乳腺癌细胞上EGFR的过度表达有关，并且 MAPK-ERK和PI3K-Akt-mTor信号通路过度激活或信号增强。我们现在有了 发现了两种对他莫昔芬治疗耐药的新的过度激活介质，它们位于 这些关键途径，我们展示了它们在抗药性中的重要性。他莫昔芬耐药的两个效应物是 翻译起始因子eIF4E的抑制物，称为4E-BP1，以及过度激活对eIF4E的磷酸化。 激活其ERK相关的激酶MNK1。两者都是现有实验药物的治疗靶点。 开发用于其他用途，具有良好的毒性特征。EIF4E包含以下基本翻译组件 将核糖体装载到mRNA上。我的团队和其他人进行的许多研究表明， EIF4E的磷酸化受ERK-MNK1途径的控制，其丰度的增加受到控制 通过mTOR/4E-BP1途径，选择性地上调特定的mRNAs的翻译 乳腺癌细胞的存活、增殖和转移。

Project Summary. Estrogen receptor positive (ER+) breast cancers comprise the majority (~70-80%) of breast cancers, the majority of late recurrences emanating from indolent or dormant breast cancer, and the majority of breast cancer deaths resulting from metastatic disease. Anti-endocrine therapy with tamoxifen remains the cornerstone of adjuvant therapy for ER+ breast cancers, particularly in premenopausal women, but also following treatment with aromatase inhibitors in the post-menopausal setting. Nevertheless, many women do not respond to tamoxifen in initial therapy, and of those that do, one third will relapse with resistant and metastatic disease within 15 years. Endocrine resistant ER+ breast cancers therefore remain one of the major causes of breast cancer metastasis and mortality. In fact, initial or acquired resistance to tamoxifen is involved in more than half of all ER+ breast cancer deaths. Reversing resistance to tamoxifen therapy is a crucial overarching breast cancer challenge. We provide preclinical research demonstrating the discovery of a crucial axis that provides tamoxifen resistance to ER+ breast cancer cells mediated by the epidermal growth factor receptor (EGFR)/estrogen receptor α (ERα) pathways, and their impact on selective mRNA translation through the kinase mTOR. Moreover, we demonstrate that there are several experimental drugs developed for other indications that can be repurposed to target this axis for the treatment of tamoxifen resistant ER+ breast cancers. Tamoxifen is an estrogen receptor antagonizing small molecule used for treatment for ER+ breast cancer worldwide. Resistance is well established to commonly involve overexpression of EGFRs on breast cancer cells, and hyper-activation or increased signaling of the MAPK-ERK and PI3K-Akt-mTOR pathways. We have now identified two novel hyperactivated mediators of resistance to tamoxifen therapy that lie at the intersection of these key pathways, and we show their importance in resistance. The two effectors of tamoxifen resistance are the inhibitor of translation initiation factor eIF4E, known as 4E-BP1, and the phosphorylation of eIF4E by hyper- activation of its ERK associated kinase, MNK1. Both are therapeutic targets for existing experimental drugs developed for other purposes with good toxicity profiles. eIF4E comprises the basic translation component for loading ribosomes onto mRNAs. Many studies by my group and others have shown that increased phosphorylation of eIF4E is controlled by the ERK-MNK1 pathway, and its increased abundance is controlled by the mTOR/4E-BP1 pathway, which selectively upregulates translation of specific mRNAs required for survival, proliferation and metastasis of breast cancer cells.