Mammary Gland Laterality in Normal and Neoplastic Development

描述(申请人提供)：乳腺癌是女性最常见的癌症类型，仅次于肺癌，是女性癌症相关死亡的主要原因。拟议的项目将解决这种疾病一个几乎没有研究过的特征：左侧乳腺肿瘤的患病率。总体假设是左侧和右侧乳腺对肿瘤的启动和/或进展具有不同程度的易感性。如果正确，差异左-右(L-R)易感性在青春期可能特别重要，当胚胎建立的原始导管网络的快速生长和重塑使乳腺非常容易受到促进肿瘤的遗传、激素和其他环境扰动的影响。为了验证这一假设，将使用三种肿瘤发展的小鼠模型：雌激素治疗的小鼠，它建立了月经初潮早期的模型，这是一个有充分证据的乳腺癌的主要风险因素；MMTV-cNeu转基因小鼠，一个经典的和广泛使用的乳腺癌发生模型；以及MMTV-Wnt1转基因小鼠，乳腺癌干细胞研究的首选模型。将从形态、细胞和分子水平系统研究L-R在乳腺发育中的差异，包括通过差异表达谱对导管网络形成的整体形态测量。将特别关注节点信号通路。节点是一种转化生长因子吗？家族成员是胚胎L-R不对称图案的主要调节者。在乳腺癌患者中，结节通路成分的表达下调与预后不良有关，这表明该通路在乳腺癌的发生中起着额外的作用。具体目标1将确定在通过雌激素暴露诱导经历早期月经初潮的小鼠的左侧和右侧乳腺中，结节通路组件和导管模式的表达是否不同。围绕青春期发育的时间进程研究将量化基因表达谱，并测量上皮干/祖细胞池、导管上皮细胞生长、存活和分支形态发生方面的假定差异。在具体目标2中，将在青春期MMTV-cNeu和MMTV-WNT1转基因小鼠中进行平行研究，以确定L-R在乳腺发育中的形态和分子差异是否在肿瘤发生的早期出现和/或变得突出。由于其他两侧配对器官的肿瘤也存在L-R偏向，而且有新的证据表明，某些癌症的5年生存率因肿瘤形成的左侧和右侧而有显著差异，因此拟议项目的意义在于，乳腺癌偏侧性的调查最终可能会改善乳腺癌患者的治疗和生存。 与公共卫生相关：拟议的项目将解决乳腺癌一个鲜为人知的方面--为什么左乳房比右乳房发生更多的肿瘤。实验将集中在青春期发育过程中起作用的基因和细胞过程，这些基因和细胞过程可能会导致左侧肿瘤的流行。这项研究的长期意义在于，它可能会提供有关正常和肿瘤乳腺发育的信息，这些信息可以用来改进目前的治疗方法或开发新的治疗方案。

DESCRIPTION (provided by applicant): Breast cancer is the most common type of cancer that occurs in women and is second only to lung cancer as the leading cause of women's cancer-related deaths. The proposed project will address a virtually unstudied feature of the disease: the left-side prevalence of breast tumors. The overall hypothesis is that the left and right mammary glands are differentially susceptible to tumor-initiation and/or progression. If correct, differential left-right (L-R) susceptibility may be particularly important during puberty, when the rapid growth and remodeling of the embryonically established, rudimentary ductal network renders the mammary glands highly vulnerable to genetic, hormonal, and other environmental perturbations that promote neoplasias. To test this hypothesis, three mouse models of neoplastic development will be used: estrogen treated mice, which model early menarche, a well documented primary risk factor for breast cancer; MMTV-cNeu transgenic mice, a classic and widely used model of breast carcinogenesis; and MMTV-Wnt1 transgenic mice, a premier model for breast cancer stem cell studies. Putative L-R differences in mammary gland development will be systematically investigated at the morphological, cellular, and molecular levels, ranging from whole mount morphometric measurements of ductal network formation through differential L-R gene expression profiles. Particular attention will be given to the nodal signaling pathway. Nodal is a TGF? family member that is a master regulator of embryonic L-R asymmetric patterning. De-regulated expression of nodal pathway components is associated with poor prognostic outcome in breast cancer patients, suggesting an additional role for this pathway in mammary gland carcinogenesis. Specific Aim 1 will determine whether expression of nodal pathway components and ductal patterning differ in the left versus right mammary glands of mice induced to undergo early menarche via estrogen exposure. Time -course studies encompassing pubescent development will quantify gene expression profiles and measure putative differences in the epithelial stem/progenitor cell pool, ductal epithelial cell growth, survival, and branching morphogenesis. In Specific Aim 2, parallel studies will be performed in pubescent MMTV-cNeu and MMTV-Wnt1 transgenic mice to determine whether morphological and molecular L-R differences in mammary gland development arise and/or become accentuated early in oncogenesis. Because L-R bias for tumor formation also occurs for cancers in other bilaterally paired organs, and because there is emerging evidence that the 5-year survival rates for some cancers significantly differ according to the left versus right side of tumor formation, the significance of the proposed project is that investigation of breast cancer laterality ultimately may lead to improvements in the treatment and survival of breast cancer patients. PUBLIC HEALTH RELEVANCE: The proposed project will address a poorly understood aspect of breast cancer-the question of why more tumors develop in the left breast than the right. Experimentation will focus on genes and cellular processes that function during pubescent development and that may predispose left-side prevalence for tumor formation. The long-term significance of this study is that it may yield information on normal and neoplastic mammary gland development that could be used to improve delivery of current therapies or development of new treatment regimes.