Role of HIC1 in suppression of breast cancer growth and tamoxifen resistance

HIC1 在抑制乳腺癌生长和他莫昔芬耐药中的作用

• 批准号: 7739691
• 负责人: SHENG WANG
• 金额: $ 21.7万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7739691
• 关键词: Antineoplastic Agents; Breast Cancer Cell; Breast Cancer Early Detection; Breast Cancer Treatment; Cells; Cessation of life; Clinical Research; Collaborations; Development; Diagnosis; Drug resistance; Early Diagnosis; Effectiveness; Epidemiologist; Estrogen Antagonists; Gene Expression; Genetic Transcription; Growth; Human; Investigation; Lead; Mediating; Methylation; Molecular; Molecular Biology; Molecular Target; Outcome; Physicians; Registries; Regulation; Research; Resistance; Role; Signal Transduction Pathway; TP53 gene; Tamoxifen; Testing; Transcription Repressor/Corepressor; Translating; Tumor Suppressor Genes; Tumor Suppressor Proteins; base; cell growth regulation; cellular development; design; gene repression; hormone therapy; improved; malignant breast neoplasm; molecular marker; novel; outcome forecast; prohibitin; promoter; public health relevance; resistance mechanism; response; treatment strategy; tumor

DESCRIPTION (provided by applicant): Estrogen antagonists comprise the most frequently used hormonal therapy for breast cancer. Tamoxifen therapy's effectiveness is limited, however, by the inevitable development of cellular resistance. The molecular mechanisms of this resistance are not defined, and this lack of information impedes the rational design of improved anti-breast cancer drugs. Our preliminary investigation led to a surprising discovery. We found that tamoxifen strongly induces the expression of silenced HIC1 tumor suppressor gene in tamoxifen-sensitive breast cancer cells, and this induction is lost in the tamoxifen-resistant breast cancer cells (even though they remain ER positive). HIC1 is found to be silenced in certain breast cancers and other forms of human tumors, probably due to heavy methylation of its promoter. A clinical study demonstrated that expression of HIC1 is associated with a good outcome in human breast cancer, which suggests the potential importance of HIC1 in early detection, diagnosis and prognosis of breast cancer. We therefore hypothesize that HIC1 is required for tamoxifen activity in breast cancer cells, and that the loss of tamoxifen-induced HIC1 gene expression represents a potential molecular mechanism for the development of tamoxifen resistance. We propose here to investigate this novel phenomenon and hypothesis at the molecular mechanistic level and test it clinically through collaborations with epidemiologists and physicians, taking advantage of the Danish Breast Cancer Collaborative Group's (DBCG) registry. This investigation may identify novel molecular markers for early breast cancer detection, diagnosis, and prognosis. The study may also lead to identification of a novel molecular target(s) for the design of improved anti-breast cancer treatment strategies. Specific Aim I. Study the role of HIC1in tamoxifen resistance. Specific Aim II. To study the molecular mechanism of HIC1-mediated transcription and growth regulation in response to tamoxifen. II-1. Determine the involvement and necessity of prohibitin in HIC1 regulation by estrogen antagonists. II-2. Determine the molecular mechanisms and the importance of the association between HIC1 and prohibitin. II-3. Study the signal transduction pathway involved in the HIC1 expression induced by estrogen antagonists. II-4. Investigate the mechanisms of HIC1 silencing in estrogen antagonist resistant breast cancer cells and tumors. PUBLIC HEALTH RELEVANCE: The most commonly used hormonal therapy for breast cancer Estrogen antagonists is limited by the inevitable development of cellular resistance. We propose here to investigate a potential molecular mechanism of this drug resistance by taking advantage of a novel discovery (lost induction of tumor suppressor HIC1 in tamoxifen resistant cells) through collaborations with epidemiologists and physicians, taking advantage of the Danish Breast Cancer Collaborative Group's (DBCG) registry (DBCG registry hereafter). This investigation may identify novel molecular markers for early breast cancer detection, diagnosis, prognosis, and for design of improved anti-breast cancer treatment strategies.

描述（由申请人提供）：雌激素拮抗剂是乳腺癌最常用的激素疗法。然而，他莫昔芬疗法的有效性受到细胞耐药性不可避免的发展的限制。这种耐药性的分子机制尚未明确，信息的缺乏阻碍了改进抗乳腺癌药物的合理设计。我们的初步调查得出了一个令人惊讶的发现。我们发现他莫昔芬强烈诱导对他莫昔芬敏感的乳腺癌细胞中沉默的 HIC1 肿瘤抑制基因的表达，而这种诱导作用在他莫昔芬耐药的乳腺癌细胞中消失（即使它们仍然是 ER 阳性）。研究发现，HIC1 在某些乳腺癌和其他形式的人类肿瘤中被沉默，这可能是由于其启动子的重甲基化所致。一项临床研究表明，HIC1的表达与人类乳腺癌的良好预后相关，这表明HIC1在乳腺癌的早期检测、诊断和预后中具有潜在的重要性。因此，我们假设 HIC1 是乳腺癌细胞中他莫昔芬活性所必需的，并且他莫昔芬诱导的 HIC1 基因表达的丧失代表了他莫昔芬耐药性发展的潜在分子机制。我们在此建议在分子机制水平上研究这一新现象和假设，并通过与流行病学家和医生的合作，利用丹麦乳腺癌合作组（DBCG）的注册进行临床测试。这项研究可能会发现用于早期乳腺癌检测、诊断和预后的新分子标记。该研究还可能导致鉴定新的分子靶点，用于设计改进的抗乳腺癌治疗策略。具体目的一、研究HIC1在他莫昔芬耐药中的作用。具体目标二。研究HIC1介导的转录和生长调节对他莫昔芬反应的分子机制。 II-1.确定抑制素在雌激素拮抗剂 HIC1 调节中的参与和必要性。 II-2.确定 HIC1 和抑制素之间关联的分子机制和重要性。 II-3.研究雌激素拮抗剂诱导HIC1表达的信号转导通路。 II-4。研究雌激素拮抗剂耐药性乳腺癌细胞和肿瘤中 HIC1 沉默的机制。公众健康相关性：乳腺癌最常用的激素疗法雌激素拮抗剂受到不可避免的细胞耐药性的限制。我们在此建议通过与流行病学家和医生合作，利用丹麦乳腺癌协作组 (DBCG) 的一项新发现（他莫昔芬耐药细胞中肿瘤抑制因子 HIC1 的诱导消失）来研究这种耐药性的潜在分子机制。 ) 注册表（以下简称 DBCG 注册表）。这项研究可能会确定用于早期乳腺癌检测、诊断、预后以及设计改进的抗乳腺癌治疗策略的新分子标记。