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（约70-80%）， 乳腺癌，大多数晚期复发起源于惰性或休眠乳腺癌， 大多数乳腺癌死亡是由转移性疾病引起的。他莫昔芬抗内分泌治疗 仍然是ER+乳腺癌辅助治疗的基石，特别是在绝经前妇女中， 而且在绝经后环境中用芳香酶抑制剂治疗后也是如此。但许多 在最初的治疗中，女性对他莫昔芬没有反应，而在那些有反应的女性中，三分之一会复发， 和转移性疾病。因此，内分泌抵抗性ER+乳腺癌仍然是最常见的乳腺癌之一。 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是 参与了超过一半的ER+乳腺癌死亡。逆转对他莫昔芬治疗的耐药性是一种 至关重要的乳腺癌挑战。 我们提供临床前研究证明了一个关键轴的发现，提供他莫昔芬 表皮生长因子受体（EGFR）/雌激素介导的对ER+乳腺癌细胞的耐药性 受体α（ERα）途径，以及它们通过激酶mTOR对选择性mRNA翻译的影响。 此外，我们证明，有几个实验性药物开发的其他适应症， 将其重新用于靶向该轴以治疗他莫昔芬耐药ER+乳腺癌。他莫昔芬是一种 雌激素受体拮抗小分子用于治疗ER+乳腺癌。 已经确立的耐药性通常涉及乳腺癌细胞上EGFR的过表达， MAPK-ERK和PI 3 K-Akt-mTOR通路的过度激活或增加的信号传导。我们现在已经 确定了两种新的对他莫昔芬治疗耐药的过度活化介质， 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子是 翻译起始因子eIF 4 E的抑制剂，称为4 E-BP 1，和eIF 4 E的磷酸化， ERK相关激酶MNK 1的激活。两者都是现有实验药物的治疗靶点 开发用于其他目的，具有良好的毒性特征。eIF 4 E包括基本的翻译组件， 将核糖体装载到mRNA上。我的团队和其他人的许多研究表明， eIF 4 E的磷酸化受ERK-MNK 1通路控制，其丰度增加受ERK-MNK 1通路控制。 通过mTOR/4 E-BP 1途径，选择性上调特定mRNA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.