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

14-3-3tau 驱动雌激素受体丧失和乳腺癌进展

• 批准号: 10655783
• 负责人: FANG-TSYR LIN
• 金额: $ 36.6万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-17 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10655783
• 关键词: 3-Dimensional; Adverse effects; Aftercare; Animal Model; Binding; Biological Markers; Breast Cancer Patient; Breast Cancer Prevention; Breast Cancer therapy; Breast cancer metastasis; Cell Mobility; Cells; Characteristics; Clinic; Clinical Trials; Collaborations; Cultured Cells; Data; Disease; Dissociation; E-Cadherin; E2F transcription factors; Effectiveness; Endocrine; Epidermal Growth Factor Receptor; Epithelium; Estrogen Receptor alpha; Estrogen Receptors; Estrogen receptor negative; Estrogen receptor positive; Event; Evolution; Exons; GATA3 gene; Genetic Transcription; Guanosine Triphosphate Phosphohydrolases; In Vitro; Intervention; Invaded; Investigation; MCF7 cell; MDA MB 231; MMP9 gene; Mammary Neoplasms; Mediating; Mesenchymal; Modeling; Neoplasm Metastasis; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacologic Actions; Phenocopy; Protein Isoforms; Regulation; Resistance; Risk; Role; Sampling; Signal Transduction; Testing; Up-Regulation; Vimentin; Xenograft Model; Xenograft procedure; breast cancer diagnosis; breast cancer progression; clinically relevant; derepression; high risk; hormone therapy; improved; in vivo; in vivo Model; inhibitor; innovation; malignant breast neoplasm; migration; new therapeutic target; novel; novel therapeutic intervention; novel therapeutics; overexpression; pharmacologic; prevent; promoter; protein expression; receptor expression; response; slug; small hairpin RNA; small molecule inhibitor; therapeutic target; three dimensional cell culture; tumor; tumor microenvironment

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.

项目概要/摘要 该项目的目标是确定新的治疗靶点，以改善乳腺癌治疗 通过防止乳腺癌扩散并恢复激素治疗的有效性。而雌激素 受体（ER）是乳腺癌最成功的治疗靶点，多达三分之一的乳腺癌丢失 ER表达因而对激素治疗没有反应。大多数 ER 丢失的机制 阴性乳腺癌仍有待研究。另一方面，尽管大多数乳腺癌是 在相对较早的阶段就被诊断出来，其中近30%的人在治疗后最终会发生转移。 我们现已确定 14-3-3tau 是体内促进乳腺癌转移和 ER 损失的关键驱动因素。 我们建立了 14-3-3tau 异种移植模型，该模型概括了雌激素受体的转移和丧失 在乳腺肿瘤中 14-3-3tau 水平高的患者中观察到的表达。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 14-3-3tau 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 3D 球体培养和动物模型以确定能够阻止这些副作用的药物。一些 所提议途径的小分子抑制剂已在临床上使用或在临床试验中进行了测试 对于其他条件。因此，如果得到证实，在患有肿瘤的患者中进行测试将是非常可行的 高水平的 14-3-3tau 存在于超过 60% 的乳腺癌中。通过14-3-3tau检查 乳腺肿瘤样本中的表达，我们也许能够识别出有患乳腺癌风险的患者 转移和对内分泌治疗失去反应。这些患者可能会受益于这些治疗 针对 14-3-3tau 下游效应子的抑制剂，以防止内分泌治疗耐药性和 转移。其中一些抑制剂已被批准用于其他疾病或可用于临床 试验。因此，该提案在提供预防乳腺癌的新治疗策略方面的潜在影响 对乳腺癌转移和逆转内分泌治疗耐药具有非常重要的意义。