The Biological Basis of Breast Density and Cancer Risk

乳房密度和癌症风险的生物学基础

• 批准号: 7028025
• 负责人: Thea D Tlsty
• 金额: $ 168.45万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-10 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7028025
• 关键词: breast density; breast neoplasms; cancer risk; clinical research; human tissue; model; tissues; breast density; breast neoplasms; cancer risk; clinical research; human tissue; model; tissues

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.

描述（由申请人提供）：虽然通过乳房X线摄影衡量的高乳房密度是乳腺癌风险的最强预测指标之一，但我们对乳腺密度的生物学基础知之甚少，或者与癌症风险增加有关。为了解决这个问题，我们需要一种综合的临床/基础科学方法来获得更准确和信息性的技术，以测量诊所中乳房X线摄影密度，对生物学产生乳腺密度的生物学有了更深入的了解，最重要的是，一种识别这种生物学的特定方面的方法，从而有助于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通过人体组织分析产生的预测，因为鼠模型提供了一个可以更容易被操纵的体内环境。我们将使用（并开发）高分辨率，体积生物成像，以在乳房密度为基础的组织学和组织组成的乳房密度和组织组成上共同注册临床X射线图像。该信息将指导我们对同一组织的分子分析，以产生乳房密度的全面分子和细胞肖像。使用体内和体外结构，遗传，分子和功能分析的人类组织的强大组合，我们将确定将高乳房密度与增加乳腺癌风险增加的候选标记。我们将使用大型，明确和独特的基于人群的同类群体来测试我们的假设并验证标记，从而增强临床医生识别那些患有乳腺癌风险的女性的能力。我们假设乳房密度升高可能是生物过程的最终结果，这些过程导致细胞细胞和/或细胞 - 特拉克卢尔矩阵（ECM）相互作用改变，并且这些因果是增加乳腺癌风险的原因。这些改变的相互作用受遗传，生理和环境因素的影响，并产生具有高乳腺密度（过量胶原蛋白，组织重塑等）特征的组织表型。在发生对组织重塑或损伤的反应的条件下，例如在乳腺发育（分支形态发生），伤口愈合或恶性肿瘤的脱瘤反应中观察到了这些表型特征。在这些过程中，“活化的基质”会导致胶原蛋白和替氏蛋白的水平升高，基质重塑和细胞周期控制的细胞周期控制，对位于内部的细胞成分。我们两名研究人员（Tlsty和Barcellos-Hoff）的先前工作表明，这种基质可以显着影响人类和鼠模型中的肿瘤发生。正确的基质上皮相互作用实际上可以抑制上皮细胞中质外表型的表达，相反，改变的基质上皮相互作用可以促进质膜塑性病变发展为恶性肿瘤的可能性。项目1中新型成像的信息的组合，项目2和4中的细胞，分子和功能分析以及项目3中的分子标记的流行病学评估有可能创建几种新的和临床上有用的，放射线图和/或分子的乳房密度测量，比乳腺X型癌症的风险更具体。