Mammary Composition Modulated by Parity, Radiation, Age and Ovarian Status

为了了解乳腺X线密度与乳腺的生物学和功能关系， 癌症风险，需要实验模型来研究受控背景下的关键特征。我们提出 致密乳房和乳腺癌风险之间的机械联系是， 导致乳腺密度增加，可通过启动邻近细胞促进恶性进展 上皮我们假设基质增加、细胞外基质重塑和 乳房X线摄影致密乳房中的分子标记物指示“活化的”基质。的一部分 在正常的基质表型连续体中，活化的基质与在活化过程中形成的基质具有相似性。 形态发生和伤口愈合。我们和其他人的实验研究表明， 非典型间质可以成为癌症进展的积极参与者。项目4将开发两个 激活的基质（AS）小鼠模型来测试这些假设。一种外源性物质，电离辐射（IR）， 和表达组成型活性转化生长因子β 1（TGF-β）的基因工程小鼠 在成纤维细胞特异性启动子（FSP-Tgf-β（223-225））上的表达将用于产生乳腺AS。放射治疗 乳腺癌会暂时增加乳房X线摄影密度。我们已经表明，IR诱导乳腺癌， 在小鼠中基质ECM重塑与在致密乳腺组织中发现的特征相似。综合这些 观察提供了IR可用作诱导小鼠乳腺癌的实验工具的基本原理。 类似于致密乳房的基质。我们已经证明TGF-β 1介导辐射诱导的ECM 重塑，并参与正常乳腺发育的卵巢激素调节。其他人已经 研究表明，TGF-β在癌症进展过程中失调。某些TGF-β 1基因多态性是 与乳腺癌风险增加有关。因此，TGF-β符合作为遗传性状的标准， 使某些妇女易患乳腺癌，以及一种由生殖调节的生长因子， 影响乳腺组织成分。通过IR和FSP-TGF-β（223-225）转基因产生的乳腺AS 将小鼠模型与项目2中确定的致密乳腺组织的特征进行比较。我们将使用 这些模型回答了以下问题：1.如何做已知的乳房密度调制器的产次，年龄和 激素状态影响AS的具体特征; 2.是上皮细胞增殖、凋亡还是形态发生 受基质激活的影响;和3. AS是否促进肿瘤进展？我们将评估标记 在项目2中确定并在项目3中测试的小鼠模型，以定义可以 用作关键流程的基准。小鼠模型可以评估生活方式对人类 变量有助于给定标记的表达。

In order to understand the biological and functional relationship between mammographic density and breast cancer risk, experimental models are needed to investigate key features in a controlled context. We propose that the mechanistic link between dense breasts and breast cancer risk is that the biological processes that lead to increased breast density can promote malignant progression by initiated cells in the adjacent epithelium. We hypothesize that features of increased stroma, remodeled extracellular matrix (ECM) and molecular markers in mammographically dense breasts are indicative of an 'activated' stroma. Part of the normal continuum of stromal phenotypes, activated stroma has similarities to the stromas formed during morphogenesis and wound healing. Our experimental studies and those of others have demonstrated that atypical stroma can become an active participant in cancer progression. Project 4 will develop two activated stroma (AS) mouse models to test these hypotheses. An exogenous agent, ionizing radiation (IR), and a genetically engineered mouse expressing constitutively active transforming growth factor beta1 (TGF-beta) on a fibroblast-specific promoter (FSP-Tgf-beta (223-225)) will be used to generate mammary AS. Radiotherapy for breast cancer transiently increases mammographic density. We have shown that IR induces mammary stromal ECM remodeling in mice similar in character to that found in dense breast tissue. Together these observations provide the rationale that IR may be used as an experimental tool to induce a mouse mammary stroma similar to that in dense breasts. We have shown that TGF-beta1 mediates radiation-induced ECM remodeling and is involved in ovarian hormone regulation of normal breast development. Others have demonstrated that TGF-beta is deregulated during cancer progression. Certain Tgf-beta1 gene polymorphisms are associated with increased breast cancer risk. Thus, TGF-beta fulfills the criteria of being a genetic trait that predisposes certain women to breast cancer as well as a hormonally regulated growth factor whose actions affect mammary tissue composition. The mammary AS produced by IR and the FSP-Tgf-beta(223-225) transgenic mouse models will be compared to the features of dense breast tissue determined in Project 2. We will use these models to answer the following: 1. How do the known breast density modulators of parity, age and hormonal status affect the specific features of AS; 2. Is epithelial proliferation, apoptosis, or morphogenesis affected by stromal activation; and 3. Does AS promote neoplastic progression? We will evaluate markers that are identified in Project 2 and tested in Project 3 in the mouse models to define commonalities that can be used as benchmarks of critical processes. Mouse models permit evaluation of how important lifestyle variables contribute to the expression of a given marker.