Oncogene susceptibility: physiological state & breast cell differentiation

癌基因易感性：生理状态

• 批准号: 8045518
• 负责人: Yi Li
• 金额: $ 30.9万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8045518
• 关键词: AXIN2 protein; Affect; Apoptosis; Appearance; Basal Cell; Breast; Breast Cancer Prevention; Cell Count; Cell Differentiation process; Cells; DNA Damage; Data; Dependence; Development; Down-Regulation; Duct (organ) structure; Ductal; Epigenetic Process; Epithelial; Epithelial Cells; Epithelium; Estrogen Receptor Status; Estrogens; Evolution; Failure; Gene Delivery; Gene Targeting; Gene Transfer Techniques; Genes; Genetic; Genus Alpharetrovirus; Hormone Responsive; Human; Individual; Infection; Lead; Lesion; Malignant Neoplasms; Mammary Neoplasms; Mammary Tumorigenesis; Mammary gland; Mediating; Methods; Modeling; Molecular; Mouse Mammary Tumor Virus; Mouse Strains; Multipotent Stem Cells; Mus; Mutation; Myoepithelial cell; Nature; Oncogenes; Oncogenic; Physiological; Predisposition; Prevention strategy; Publishing; Signal Transduction; Somatic Gene Therapy; Staging; Stem cells; Techniques; Testing; Time; Transgenes; Transgenic Mice; Transgenic Model; Transgenic Organisms; Trees; Work; carcinogenesis; cell type; deprivation; in vivo; malignant breast neoplasm; mammary epithelium; mammary gland development; overexpression; prevent; progenitor; promoter; public health relevance; receptor; response; stem; tumor; tumorigenesis; tumorigenic

DESCRIPTION (provided by applicant): The mammary ductal tree is comprised of stem cells, progenitor cells, and more differentiated epithelial and myoepithelial cells. Stem and progenitor cells are increasingly thought to be the primary targets of tumorigenesis, and indeed mammary tumors initiated by oncogenes such as Wnt-1 contain a mix of cell types implying that they arose from multipotent progenitors. However, tumors initiated by other important oncogenes such as ErbB2 usually do not contain mixed cell types, suggesting that they might originate from transformation of more differentiated cells. Furthermore, these tumors differ in their estrogen receptor status, so that the dependence on estrogen for tumor development may also differ. To test rigorously whether different oncogenes induce tumors preferentially from different mammary cell differentiation states, we use the avian retrovirus (RCAS) somatic gene transfer technique to target cells transgenically engingeered to express the gene encoding the RCAS receptor TVA - we were the first to adapt this technique to the mammary gland, and have already developed several mouse strains expressing tva from different mammary cell types and differentiation stages and begun to study tumor formation induced in these strains by several oncogenes carried by RCAS. Our preliminary data strongly suggest the hypothesis that different oncogenes do indeed prefer to induce tumors from different cell types and differentiation states in the mammary gland. Because understanding different paths to breast cancer evolution at both molecular and cellular levels could be critical for devising early prevention strategies, we propose here to use our uniquely suited models to: (1) determine whether differentiated mammary cells are more susceptible than progenitor cells (defined by new, more selective promoters) to tumor induction by ErbB2, and whether this susceptibility is due to the failure of the more differentiated cells to erect an oncogenic barrier involving the DNA damage response; (2) investigate whether mammary progenitor cells are more susceptible to induction of early lesions and tumors by Wnt-1, and what molecular network in the progenitor cells is preferentially activated by Wnt signaling to accelerate tumor development; and (3) determine how estrogen (or estrogen deprivation) affects tumor evolution induced by ErbB2 vs. Wnt in differentiated vs. progenitor cells, and which molecular mechanisms are involved in this estrogen dependence. PUBLIC HEALTH RELEVANCE: The breast ducts in which breast cancer arises are lined with at least two kinds of mature epithelial cells, but also contain small numbers of stem cells that can divide to renew themselves and can also generate progenitor cells and new mature cells. Many people have begun to think that cancer arises from an oncogenic mutation in the stem cells, but our evidence suggests that while this is true for some important oncogenes like Wnt, others like ErbB2 (Her2) may preferentially initiate tumors in mature cells. If we knew why different oncogenes work best in different cell types, and why some but maybe not others are dependent on estrogen, we could more accurately define cell-type-specific treatment targets and devise better early prevention strategies.

描述（由申请人提供）：乳腺导管树由干细胞、祖细胞和更分化的上皮细胞和肌上皮细胞组成。干细胞和祖细胞越来越多地被认为是肿瘤发生的主要靶点，实际上，由癌基因如Wnt-1引发的乳腺肿瘤含有多种细胞类型，这意味着它们来自多能祖细胞。然而，由其他重要的癌基因如ErbB 2引发的肿瘤通常不包含混合细胞类型，这表明它们可能起源于更分化的细胞的转化。此外，这些肿瘤的雌激素受体状态不同，因此肿瘤发展对雌激素的依赖性也可能不同。 为了严格测试不同的癌基因是否优先从不同的乳腺细胞分化状态诱导肿瘤，我们使用禽类逆转录病毒（RCAS）体细胞基因转移技术来靶向经转基因工程改造以表达编码RCAS受体TVA的基因的细胞-我们是第一个将这种技术应用于乳腺的人，并且已经开发了几种表达来自不同乳腺细胞类型和分化阶段的tva的小鼠品系，并开始研究由RCAS携带的几种癌基因在这些品系中诱导的肿瘤形成。我们的初步数据有力地表明了这样的假设，即不同的癌基因确实倾向于从乳腺中不同的细胞类型和分化状态诱导肿瘤。 由于在分子和细胞水平上了解乳腺癌演变的不同途径对于制定早期预防策略至关重要，因此我们建议使用我们独特适合的模型：（1）确定分化的乳腺细胞是否比祖细胞更易感（由新的、更有选择性的启动子定义）对ErbB 2的肿瘤诱导，以及这种易感性是否是由于更分化的细胞未能建立涉及DNA损伤反应的致癌屏障;（2）研究乳腺祖细胞是否对Wnt-1诱导的早期病变和肿瘤更敏感，以及祖细胞中什么样的分子网络优先被Wnt信号激活以加速肿瘤的发展;和（3）确定雌激素（或雌激素剥夺）如何影响分化细胞与祖细胞中ErbB 2与Wnt诱导的肿瘤演变，以及哪些分子机制参与这种雌激素依赖性。 公共卫生关系：乳腺癌发生的乳腺导管内衬有至少两种成熟的上皮细胞，但也含有少量的干细胞，这些干细胞可以分裂自我更新，也可以产生祖细胞和新的成熟细胞。许多人已经开始认为癌症是由干细胞中的致癌突变引起的，但我们的证据表明，虽然这对一些重要的致癌基因如Wnt是正确的，但其他如ErbB 2（Her 2）可能优先在成熟细胞中引发肿瘤。如果我们知道为什么不同的癌基因在不同的细胞类型中发挥最佳作用，以及为什么有些癌基因（但可能不是其他癌基因）依赖于雌激素，我们就可以更准确地定义细胞类型特异性治疗靶点，并设计出更好的早期预防策略。