Toward a transcription therapy for breast cancer

乳腺癌转录疗法

• 批准号: 7099195
• 负责人: MESUT MUYAN
• 金额: $ 27.69万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-03 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7099195
• 关键词: breast neoplasms; estrogens; genes; ligands; model; motivation; role

DESCRIPTION (provided by applicant): Toward a transcription therapy for breast cancer. The development of breast cancer is the consequence of uncontrolled growth of breast-ductal epithelial cells. Estrogen hormones, particularly 17beta-estradiol (E2), within the context of interrelated growth signaling pathways play critical roles for the initiation and development of breast cancer. The E2 signaling is primarily conveyed by the transcription factors estrogen receptors (ERs) alpha and beta. E2-ER mediates genomic and non-genomic events that orchestrate cell proliferation, differentiation and death. The interaction of E2-ER with specific DNA sequences, estrogen responsive elements (EREs), constitutes one primary genomic signaling. The E2-ER-mediated events are also affected by intracellular signaling pathways that cross-talk with ER and mutant ERs. Approaches to reduce/ablate the circulating E2 or to alter/prevent ER function constitute the current experimental and therapeutic modalities. Perturbations of the estrogen/ER environment are initially successful in the remission of established tumors. However, many breast tumors are not responsive or eventually develop resistance to these therapies. The absence/loss of ER expression, aberrant signaling pathways and/or variant ERs are thought to circumvent the need for ligand-ER mediated events rendering such approaches ineffective. We sought to overcome the limitations imposed by ligand, dimerization and ER-subtype in E2 signaling by specifically regulating the ERE-driven gene network. The modular nature of ER allowed us to design a monomeric ERE binding module by co-joining two DNA binding domains with the hinge domain (CDC). Integration into this CDC module of strong activation domains from other transcription factors generated constitutive ERE binding activators that specifically induced ERE-driven gene expression independent of ligand, dimerization, ER-subtype, and cell-context. We predict that the CDC module may also be used to generate potent ERE binding repressers. To effectively assess the impact of ERE binding transregulators on gene expression and subsequent alterations in cell phenotypes in vitro and in vivo, we propose to establish an adenoviral gene delivery system. Using this system, we will also identify the ERE-driven genes by a gene array approach. We anticipate that findings will be critical for the identification of new therapeutic targets, the development of prognostic tools and of a novel "transcription therapy" for breast cancer.

描述（由申请人提供）：迈向乳腺癌的转录疗法。乳腺癌的发育是胸腔外皮细胞不受控制的生长的结果。在相互关联的生长信号通路的背景下，雌激素激素，尤其是17beta-雌二醇（E2）在乳腺癌的开始和发育中起着关键作用。 E2信号主要由转录因子雌激素受体（ERS）alpha和beta传达。 E2-ER介导编排细胞增殖，分化和死亡的基因组和非基因组事件。 E2-ER与特异性DNA序列（雌激素反应元件（ERES））的相互作用构成一个主要的基因组信号传导。 E2-ER介导的事件还受到与ER和突变ER的串扰的细胞内信号通路的影响。减少/消融循环E2或更改/预防ER功能的方法构成了当前的实验和治疗方式。雌激素/ER环境的扰动最初是在缓解已建立肿瘤方面成功的。但是，许多乳腺肿瘤没有反应或最终对这些疗法产生抗性。人们认为，ER表达，异常信号通路和/或变体ER的缺失/丧失被认为可以规定对这种方法无效的配体介导的事件的需求。我们试图通过特异性调节ERE驱动的基因网络来克服E2信号中配体，二聚化和ER-SUBTYPE所施加的局限性。 ER的模块化性质使我们能够通过将两个DNA结合域与铰链结构域（CDC）共同加入单体ERE ERE结合模块。从其他转录因子产生的强大激活域的CDC模块中积分，产生了本构的ERE ERE结合激活剂，该激活因子特别诱导了ERERE驱动的基因表达，独立于配体，二聚体，ER-SUBTYPE和细胞 - 封闭式。我们预测CDC模块也可以用于生成有效的结合阻遏物。为了有效地评估ERE结合转化剂对体外和体内细胞表型的随后改变的影响，我们建议建立腺病毒基因递送系统。使用该系统，我们还将通过基因阵列方法识别ERE驱动的基因。我们预计发现，发现对于鉴定新的治疗靶标，预后工具的发展以及用于乳腺癌的新型“转录疗法”至关重要。