Mammary Gland Laterality in Normal and Neoplastic Development

描述（由申请人提供）：乳腺癌是发生在女性中最常见的癌症类型，是仅次于肺癌的第二大女性癌症相关死亡原因。拟议的项目将解决该疾病的一个几乎未被研究的特征：乳房肿瘤的左侧患病率。总的假设是，左右乳腺对肿瘤发生和/或进展的易感性不同。如果正确的话，在青春期左右（L-R）的差异易感性可能特别重要，因为此时胚胎建立的初级导管网络快速生长和重塑，使得乳腺极易受到遗传、激素和其他环境扰动的影响，从而促进肿瘤的发生。为了验证这一假设，将使用三种小鼠肿瘤发展模型：雌激素治疗的小鼠，其模型早期初潮，这是乳腺癌的主要危险因素；MMTV-cNeu转基因小鼠，乳腺癌发生的经典和广泛应用的模型；以及MMTV-Wnt1转基因小鼠，这是乳腺癌干细胞研究的首要模型。在乳腺发育中假定的L-R差异将在形态学、细胞和分子水平上进行系统的研究，范围从导管网络形成的整体形态测量到差异的L-R基因表达谱。我们将特别关注节点信号通路。淋巴结是TGF？是胚胎L-R不对称模式的主要调节者。淋巴结通路成分的表达失调与乳腺癌患者预后不良有关，这表明该通路在乳腺癌变中起着额外的作用。特异性目的1将确定通过雌激素暴露诱导小鼠早期月经初潮的左右乳腺中淋巴结通路成分和导管模式的表达是否不同。围绕青春期发育的时间过程研究将量化基因表达谱，并测量上皮干细胞/祖细胞池、导管上皮细胞生长、存活和分支形态发生的假定差异。在Specific Aim 2中，将在青春期MMTV-cNeu和MMTV-Wnt1转基因小鼠中进行平行研究，以确定乳腺发育中的形态和分子L-R差异是否在肿瘤发生早期出现和/或加剧。由于肿瘤形成的L-R偏倚也发生在其他双侧配对器官的癌症中，并且由于有新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，因此本项目的意义在于对乳腺癌侧侧性的研究最终可能导致乳腺癌患者的治疗和生存的改善。

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.