Breast microcalcifications and their role in breast cancer bone metastasis

描述（申请人提供）：乳腺癌经常转移到骨骼，导致骨溶解和临床预后差；然而，由于缺乏适当的模型系统，羟基磷灰石（HA）——乳腺微钙化的关键成分（即乳腺癌的负面预后因素）和骨矿物质基质在这一过程中的潜在作用仍不清楚。肿瘤存在时，透明质酸的物理化学性质（如结晶度、化学组成、大小和纵横比）随原发（乳腺）和继发（骨）部位的疾病状态而变化。指导当前研究者的总体假设是：肿瘤介导的透明质酸材料特性的改变通过在原发部位诱导骨转移表型来增强乳腺癌骨转移。这些细胞反过来促进转移前骨重塑，最终促进骨定植。我们之前已经开发了含矿物质的3-D肿瘤模型，它允许测试HA在乳腺癌扩散到骨骼中的物理化学性质的重要性。使用该系统，结合先进的材料表征技术，我们将测试三个子假设：1)与更侵袭性乳腺癌相关的微钙化中的透明质酸的特征是尺寸和结晶度增加，并导致乳腺癌细胞骨转移特性的上调，部分原因是不同的非特异性蛋白质吸附；

DESCRIPTION (provided by applicant): Breast cancer frequently metastasizes to bone where it leads to osteolysis and poor clinical prognosis; however, the underlying roles of hydroxyapatite (HA) - a key component of breast microcalcifications (i.e., a negative prognostic factor for breast cancer) and the bone mineral matrix - remain unclear in this process, due in part to a lack of appropriate model systems. In the presence of a tumor, the physicochemical properties of HA (e.g., crystallinity, chemical composition, size, and aspect ratio) vary with disease state at both the primary (breast) and secondary (bone) sites. The overall hypothesis guiding the current investigator is: tumor-mediated changes to HA materials properties enhance breast cancer metastasis to bone by inducing a bone-metastatic phenotype at the primary site. These cells, in turn, promote premetastatic bone remodeling, which ultimately fosters bone colonization. We have previously developed mineral-containing 3-D tumor models, which permit testing of the importance of the physicochemical properties of HA in breast cancer spreading to bone. Using this system, coupled with advanced materials characterization techniques, we will test three subhypotheses: 1) HA in microcalcifications associated with more aggressive breast cancer is characterized by increased size and crystallinity and leads to the up-regulation of bone metastatic properties in breast cancer cells due in part to varied non-specific protein adsorption; 2) HA in the bones of tumor-bearing mice is characterized by decreased size and crystallinity even prior to metastatic colonization. These changes favor tumor cell seeding and growth, which are mediated by tumor-secreted endocrine signals that differentially regulate bone cell behavior; 3) Increased bone-metastatic potential of breast cancer cells due to interactions with HA enhances premetastatic bone remodeling, which, in turn, increases the osteotropism of breast cancer cells; pharmacological intervention with this process can decrease bone metastasis. There are three specific aims designed to test these hypotheses: In Aim 1, we will characterize HA materials properties in breast microcalcifications, and assess their impact on the bone-metastatic potential of tumor cells. In Aim 2, we will characterize HA materials properties in the bones of tumor-bearing animals pre- and post-colonization with breast cancer cells, and identify their role in secondary tumor formation. In Aim 3, we will assess the integrated effects of breast microcalcifications and premetastatic bone remodeling on breast cancer bone metastasis. The novel combination of cancer biology with engineering and materials science approaches will result in a highly reproducible and pathologically relevant culture platform that will allow us to deconvolute the complexity of bone metastasis and identify molecular targets for improved therapies. By elucidating the importance of materials-based mechanisms, the proposed research has the potential to challenge the currently accepted paradigm of bone metastasis as a disease that is solely mediated by cellular and molecular changes.