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

项目摘要： 该项目的主要目标是描述一种新的治疗靶点， 改进乳腺癌治疗方法防止乳腺癌扩散和复发 激素治疗的有效性尽管大多数乳腺癌的诊断 在相对早期阶段，其中近30%最终会发生转移， 尽管治疗。导致乳腺癌转移的关键因素仍然是 发现了另一方面，虽然雌激素受体（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 表达，因此不响应内分泌治疗。ER损失的机制 大多数ER阴性乳腺癌还有待研究。我们现在已经 确定了一种信号分子14-3-3τ作为促进乳腺癌的关键驱动因素， 转移和ER丢失。我们提出（1）用14-3-3τ来模拟人乳腺癌 进展，（2）确定ERα36在乳腺癌中14-3-3τ促进的ER丢失中的作用 癌症，和（3）利用我们已经建立的动物模型来测试抑制剂 靶向14-3-3τ通路，以预防乳腺癌转移并恢复乳腺癌细胞的功能。 对激素治疗的反应。一些小分子抑制剂的建议 这些途径已经在临床上可用，或者已经在其他临床试验中进行了测试。 条件因此，如果得到证实，将其在患有以下疾病的患者中进行测试是非常可行的。 肿瘤携带高水平的14-3-3τ。通过对14-3-3τ的检查 在乳腺肿瘤样本中的表达，我们也许能够识别出 有发生转移和对内分泌治疗失去反应的风险。这些 患者可以从这些靶向下游的抑制剂的治疗中获益， 14-3-3τ抑制乳腺癌转移。这一潜在影响 提供预防乳腺癌转移的新治疗策略的建议 对恢复ER（-）乳腺癌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.