New mechanisms of breast cancer metastasis and loss of estrogen receptor driven by 14-3-3

项目总结： 该项目的主要目标是确定一种新的治疗靶点，以便 改进乳腺癌治疗方法防止乳腺癌扩散和恢复 激素治疗的有效性。尽管大多数乳腺癌都被诊断出 在相对较早的阶段，近30%的人最终会在 尽管接受了治疗。推动乳腺癌转移的关键因素仍然是 被发现了。另一方面，雌激素受体(ER)是最成功的 乳腺癌的治疗靶点，多达三分之一的乳腺癌失去ER 因此，内分泌治疗不起作用。内质网丢失机制的研究进展 大多数ER阴性的乳腺癌也仍有待调查。我们现在有了 确定信号分子14-3-3τ是促进乳腺癌的关键驱动因素 转移和内质网丢失。我们建议(1)使用14-3-3τ来建立人乳腺癌模型 进展，(2)确定ERα36在14-3-3τ促进的乳腺ER丢失中的作用 癌症，以及(3)利用我们建立的动物模型来测试抑制剂 靶向14-3-3τ通路预防乳腺癌转移和修复 对激素治疗的反应。一些小分子抑制剂对建议的 这些途径已经在临床上可用，或在临床试验中用于其他 条件。因此，如果得到证实，在患有慢性阻塞性肺病的患者身上进行测试是非常可行的。 具有高水平14-3-3τ的肿瘤。通过对14-3-3τ的检查 在乳腺肿瘤样本中的表达，我们可能能够识别出 有发生转移和对内分泌治疗失去反应的风险。这些 患者可能从这些针对下游的抑制剂的治疗中受益 14-3-3τ的效应物预防乳腺癌转移这可能带来的影响 关于提供预防乳腺癌转移的新治疗策略的建议 恢复ER(-)乳腺癌患者的内分泌敏感性具有重要意义。

Project Summary: The main goal of this project is to characterize a new therapeutic target in order to improve breast cancer therapy in preventing breast cancer from spreading and restoring the effectiveness of hormone therapy. Despite most breast cancers are diagnosed during relatively early stage, nearly 30% of them will eventually develop metastasis in spite of treatment. The key factors that drive breast cancer metastasis remain to be discovered. On the other hand, while estrogen receptor (ER) is the most successful therapeutic target in breast cancer, up to one-third of breast cancers lose ER expression, thus do not respond to endocrine therapy. The mechanisms for ER loss in the majority of ER-negative breast cancers also remain to be investigated. We have now identified a signaling molecule 14-3-3τ as a key driver that promotes breast cancer metastasis and ER loss. We propose (1) to use 14-3-3τ to model human breast cancer progression, (2) to determine a role for ERα36 in 14-3-3τ-promoted ER loss in breast cancer, and (3) to utilize the animal model that we have established to test the inhibitors targeting the 14-3-3τ pathways to prevent breast cancer metastasis and restore the response to hormone therapy. Some small molecule inhibitors for the proposed pathways have been available in clinics or been tested in clinical trials for other conditions. Thus, if confirmed, it would be quite feasible to test them in patients with tumors harboring high levels of 14-3-3τ. Through the examination of the 14-3-3τ expression in the breast tumor samples, we might be able to identify the patients who are at risk of developing metastasis and losing response to endocrine therapy. These patients may benefit from treatment with these inhibitors targeting the downstream effectors of 14-3-3τ to prevent breast cancer metastasis. The potential impact of this proposal in providing a novel therapeutic strategy to prevent breast cancer metastasis and to restore endocrine sensitivity in ER(-) breast cancer is very significant.