Biological Basis of Breast Density and Cancer Risk

描述（由申请人提供）：虽然乳房x线摄影测量的高乳腺密度是乳腺癌风险的最强预测因素之一，但我们对乳腺密度的生物学基础知之甚少，也不知道它为什么或如何与癌症风险增加相关。为了解决这个问题，我们需要结合临床/基础科学的方法，以获得更准确和信息丰富的技术来测量临床乳房x线摄影密度，更全面地了解产生乳房密度的生物学，最重要的是，找到一种方法来确定这种生物学的特定方面，这些方面会增加人类乳腺癌的风险。我们的多学科研究将首先检查人体组织，以解决乳腺密度的组织学和病理生理基础。为了扩展这些研究，我们将使用动物模型来测试由人体组织分析产生的预测，因为小鼠模型提供了更容易操作的体内设置。我们将使用（并开发）高分辨率，体积生物成像，将乳腺密度的临床x射线图像与乳腺密度的组织学和组织组成进行空间联合注册。这些信息将指导我们对同一组织的分子分析，以产生乳腺密度的综合分子和细胞肖像。通过对人体组织的体内和体外结构、遗传、分子和功能分析的强大结合，我们将确定将高乳腺密度与乳腺癌风险增加联系起来的候选标记物。我们将使用大型的、定义明确的、独特的基于人群的队列来验证我们的假设和验证标记，这些标记将提高临床医生识别乳腺癌风险显著增加的女性的能力。我们假设乳腺密度增加可能是生物过程的最终结果，导致细胞-细胞和/或细胞-细胞外基质（ECM）相互作用的改变，这些是乳腺癌风险增加的原因。这些改变的相互作用受到遗传、生理和环境因素的影响，并产生具有高乳腺密度特征的组织表型（过多的胶原蛋白、组织重塑等）。这些表型特征在组织重塑或损伤反应发生的情况下被观察到，如乳腺发育（分支形态发生）、伤口愈合或恶性肿瘤的结缔组织增生反应。在这些过程中，“活化的基质”导致胶原蛋白和腱素水平的增加，基质重塑和细胞周期控制的改变。我们的两位研究者（Tlsty和Barcellos-Hoff）先前的工作表明，这种基质可以显著影响人类和小鼠模型的肿瘤发生。适当的间质-上皮相互作用实际上可以抑制上皮细胞中瘤前表型的表达，相反，改变间质-上皮相互作用可以促进瘤前病变进展为恶性的可能性。项目1中的新成像信息，项目2和项目4中的细胞、分子和功能分析以及项目3中分子标记的流行病学评估相结合，有可能创造出几种新的和临床有用的乳腺密度放射学和/或分子测量方法，这些方法在估计癌症风险方面比乳房x线摄影密度更具体。

DESCRIPTION (provided by applicant): While high breast density, as measured by mammography, is one of the strongest predictors of breast cancer risk, we know little about the biological basis of breast density or why or how it is associated with increased cancer risk. To address this problem we need a combined clinical/ basic science approach to obtain more accurate and informative techniques to measure mammographic density in the clinic, a fuller understanding of the biology that generates breast density and, most importantly, a way to identify specific aspects of this biology that contribute to increased risk for human breast cancer. Our multidisciplinary investigation will first and foremost examine human tissue to address the histologic and pathophysiologic basis of breast density. To extend these studies, we will use animal models to test predictions generated by the analysis of human tissues since murine models provide an in vivo setting that can be more easily manipulated. We will use (and develop) high-resolution, volumetric bio-imaging to spatially co-register clinical X-ray images of breast density to the histology and tissue composition that underlies breast density. This information will guide our molecular analysis of the same tissue to produce a comprehensive molecular and cellular portrait of breast density. Using a powerful combination of in vivo and in vitro structural, genetic, molecular and functional analyses of human tissue, we will identify candidate markers that link high breast density with an increased risk for breast cancer. We will use large, well-defined and unique population-based cohorts to test our hypotheses and validate markers that would enhance a clinician's ability to identify those women at significantly increased risk for breast cancer. We hypothesize that increased breast density may be the end result of biologic processes that result in altered cell-cell and/or cell-extracelluar matrix (ECM) interactions and that these are causal for increased breast cancer risk. These altered interactions are influenced by genetic, physiologic and environmental factors and generate the tissue phenotypes that are characteristic of high breast density (excess collagen, tissue remodeling, etc.). These phenotypic characteristics have been observed in conditions where response to tissue remodeling or damage is occurring such as in mammary gland development (branching morphogenesis), wound healing or the desmoplastic reaction of malignancies. In these processes, "activated stroma" results in increased levels of collagen and tenascin, stromal remodeling and altered cell cycle control for cellular components located within. Prior work from two of our Investigators (Tlsty and Barcellos-Hoff) has shown that such stroma can dramatically influence tumorigenesis in both human and murine models. Proper stromal-epithelial interactions can actually suppress the expression of preneoplastic phenotypes in epithelial cells and conversely, altered stromal-epithelial interactions can promote the probability that preneoplastic lesions progress to malignancy. The combination of information from the novel imaging in Project 1, the cellular, molecular and functional analyses in Projects 2 and 4 and the epidemiological assessment of molecular markers in Project 3 has the potential to create several new and clinically useful, radiographic and/or molecular measures of breast density that are more specific than mammographic density for estimating cancer risk.