Cellular Mechanisms of Bone Quality in Metastatic Breast Cancer

残骨质量受损以及骨量减少在患者中很常见。 患有晚期乳腺癌，并导致骨骼并发症，影响生活质量， 如骨痛和病理性骨折。随着患者的生活，这一点变得越来越重要 转移性疾病的时间更长，目前的治疗方法如芳香酶使其变得复杂 抑制剂。我们的假设是，尽管转移部位的骨丢失是由 乳腺癌细胞诱导的破骨细胞活性、残留骨的质量 肿瘤-骨界面由成骨细胞分化决定，成骨细胞分化经常受到损害 在转移性乳腺癌中。此外，我们认为这是环境的结果 转移性乳腺癌微环境中丰富的转化生长因子β浓度 骨中的细胞，并可通过抗TGFp治疗而减少，我们假设会 促进成骨细胞分化，提高骨中骨质量。 为了验证这一假设，我们计划研究转化生长因子在成骨细胞中的特定作用。 乳腺患者和临床前模型的分化、骨结构和质量 癌症转移。临床前模型将为设计 临床研究。在目标1中，我们将确定受损的TGFp信号在 成骨细胞通过条件基因敲除转化生长因子受体激酶的小鼠，以及 用包括拉曼光谱、原子光谱在内的最先进技术评估骨骼质量 力显微镜和UCT。在目标2中，我们将确定抗TGFp治疗的效果。 在影响肿瘤负担的同时，使用抗转化生长因子-β抗体改善骨质量， 荷人乳腺癌小鼠的成骨细胞分化和骨结构， 指导目标3中临床研究的设计，并提供有关以下方面的信息 受益于抗TGFp治疗。在目标3中，我们将确定抗TGFp的作用 转移性乳腺癌患者的I期研究中的骨骼抗体。这些研究 关注乳腺癌的一个重要并发症，该并发症显著影响乳腺癌的质量 对晚期疾病患者的生活，应具有重要的治疗意义。

Impaired quality of residual bone, as well as decreased bone amount, is common in patients with advanced breast cancer, and leads to skeletal complications that impair quality of life, such as bone pain and pathologic fracture. This is of increasing importance as patients live longer with metastatic disease, and is compounded by current therapies such as aromatase inhibitors. Our hypothesis is that whereas bone loss at the metastatic site is determined by osteoclast activity induced by the breast cancer cells, the quality of the residual bone at the tumor-bone interface is determined by osteoblast differentiation, which is frequently impaired in metastatic breast cancer. Furthermore, we propose that this is a consequence of ambient TGF-¿ concentrations which are enriched in the microenvironment of metastatic breast cancer cells in bone, and can be decreased by anti-TGFp therapy, which we hypothesize will enhance osteoblast differentiation as well as improving bone quality in bone. To test this hypothesis, we plan to investigate the specific role of TGFp in osteoblast differentiation, bone structure and quality both in patients and preclinical models of breast cancer metastasis. Preclinical models will provide important information for the design of clinical studies. In Aim 1, we will determine the effects of impaired TGFp signaling in osteoblasts by the use of mice with conditional knockout of the TGF-¿ receptor kinase, and assess bone quality by state-of-the-art techniques including Raman spectroscopy, Atomic Force microscopy and uCT. In Aim 2, we will determine the effects of anti-TGFp therapy using anti-TGF-¿ antibodies on bone quality, in parallel with effects on tumor burden, osteoblast differentiation and bone structure in the mice bearing human breast cancer cells, to guide the design of clinical studies in Aim 3, and provide information on the spectrum of benefits from anti-TGFp therapy. In Aim 3, we will determine the effects of anti-TGFp antibodies on bone in a phase I study in patients with metastatic breast cancer. These studies focus on an important complication of breast cancer that markedly influences the quality of life in patients with advanced disease, and should have important therapeutic implications.