Oncogene susceptibility: physiological state & breast cell differentiation

描述(申请人提供)：乳腺导管树由干细胞、祖细胞和更多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被认为是肿瘤发生的主要靶点，事实上，由WNT-1等癌基因引发的乳腺肿瘤包含多种细胞类型，这意味着它们来自多能祖细胞。然而，由ErbB2等其他重要癌基因启动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多分化的细胞的转化。此外，这些肿瘤的雌激素受体状态不同，因此对雌激素在肿瘤发展中的依赖也可能不同。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转基因工程细胞表达RCAS受体TVA基因-我们第一个将该技术应用于乳腺，并已经培育了几个表达不同乳腺细胞类型和分化阶段的TVA的小鼠株，并开始研究RCAS携带的几个癌基因在这些株系中的诱导肿瘤形成。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更倾向于诱导乳腺中不同细胞类型和分化状态的肿瘤。由于在分子和细胞水平上了解乳腺癌发生的不同途径对于设计早期预防策略至关重要，我们建议使用我们独特的合适的模型来：(1)确定分化的乳腺细胞是否比前体细胞(由新的、更具选择性的启动子定义)对ErbB2诱导肿瘤更敏感，以及这种敏感性是否是由于更多分化的细胞未能建立涉及DNA损伤反应的癌基因屏障；(2)研究乳腺前体细胞是否更容易被WNT-1诱导早期病变和肿瘤，以及前体细胞中的哪个分子网络优先被Wnt信号激活以加速肿瘤的发展；以及(3)确定雌激素(或雌激素剥夺)如何影响ErbB2与Wnt在分化的祖细胞和分化的祖细胞中诱导的肿瘤进化，以及这种雌激素依赖的分子机制。 与公共卫生相关：发生乳腺癌的乳腺导管内至少有两种成熟的上皮细胞，但也含有少量干细胞，这些干细胞可以分裂更新，还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Wnt等一些重要的癌基因确实如此，但其他一些基因，如ErbB2(Her2)，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好的作用，以及为什么一些而不是其他的依赖于雌激素，我们就可以更准确地定义针对细胞类型的治疗目标，并设计出更好的早期预防策略。

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.