14-3-3tau drives estrogen receptor loss and breast cancer progression

项目概要/摘要 该项目的目的是描述一种新的治疗靶点，以改善乳腺癌治疗 通过防止乳腺癌扩散和恢复激素治疗的有效性。而雌激素 受体（ER）是乳腺癌中最成功的治疗靶点，高达三分之一的乳腺癌失去了ER受体。 ER表达，因此对激素治疗没有反应。大多数ER-1细胞中ER损失的机制 阴性乳腺癌仍有待研究。另一方面，尽管大多数乳腺癌是 在相对早期诊断的患者中，近30%在治疗后最终会发生转移。 我们现在已经确定14-3- 3 tau是体内促进乳腺癌转移和ER丢失的关键驱动因素。 我们建立了一个14-3- 3 tau异种移植模型，该模型再现了转移和雌激素受体丢失 如在乳腺肿瘤中具有高水平14-3- 3 tau的患者中所见。我们还开发了一种新的 ER丢失的体外3D乳腺癌球体模型。该提案将研究14-3- 3 tau如何促进 乳腺癌从ER阳性到ER阴性的演变和内分泌抵抗，并使用已建立的 三维球体培养和动物模型，以确定能够阻断这些不良反应的药物。一些 针对所提出的途径的小分子抑制剂已经在临床上可用或在临床试验中测试 其他条件。因此，如果得到证实，将它们用于患有肿瘤的患者是非常可行的。 高水平的14-3- 3 tau，在超过60%的乳腺癌中发现。通过对14-3- 3 tau的检测， 在乳腺肿瘤样本中的表达，我们可能能够识别出有发展风险的患者。 转移和对内分泌治疗失去反应。这些患者可能受益于这些治疗 靶向14-3- 3 tau的下游效应物以防止内分泌治疗抗性的抑制剂， 转移这些抑制剂中的一些已经被批准用于其他疾病或可用于临床 审判因此，这一提议在提供一种新的治疗策略以预防乳腺癌方面的潜在影响是显而易见的。 肿瘤转移和逆转乳腺癌内分泌治疗耐药是非常重要的。

Project Summary/Abstract The objective of this project is to characterize a new therapeutic target in order to improve breast cancer therapy by preventing breast cancer from spreading and restoring the effectiveness of hormone therapy. While estrogen receptor (ER) is the most successful therapeutic target in breast cancer, up to one-third of breast cancers lose ER expression and thus do not respond to hormone therapy. The mechanisms for ER loss in the majority of ER- negative breast cancers remain to be investigated. On the other hand, despite most breast cancers are diagnosed during relatively early stage, nearly 30% of them will eventually develop metastasis after treatment. We have now identified 14-3-3tau as a key driver that promotes breast cancer metastasis and ER loss in vivo. We have established a 14-3-3tau xenograft model which recapitulates metastasis and loss of estrogen receptor expression as seen in patients with high levels of 14-3-3tau in their breast tumors. We also developed a new in vitro 3D breast cancer spheroid model of ER loss. This proposal will investigate how 14-3-3tau promotes the evolution of breast cancer from ER-positive to ER-negative and endocrine resistance, and use the established 3D spheroid culture and animal models to identify the drugs capable of blocking these adverse effects. 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 14-3-3tau, which are found in over 60% of breast cancer. Through the examination of 14-3-3tau 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 14-3-3tau to prevent endocrine therapy resistance and metastasis. Some of these inhibitors have already been approved for other diseases or are available in clinical trials. Thus, the potential impact of this proposal in providing a novel therapeutic strategy to prevent breast cancer metastasis and to reverse endocrine therapy resistance in breast cancer is very significant.