Cellular Mechanisms of Bone Quality in Metastatic Breast Cancer

患者的残余骨质量受损以及骨量减少是常见的 患有晚期乳腺癌，并导致骨骼并发症，影响生活质量， 例如骨痛和病理性骨折。随着患者的生活越来越重要， 更长的转移性疾病，并与目前的治疗，如芳香化酶 抑制剂的我们的假设是，尽管转移部位的骨丢失是由以下因素决定的： 乳腺癌细胞诱导的破骨细胞活性， 肿瘤-骨界面由成骨细胞分化决定，成骨细胞分化经常受损 在转移性乳腺癌中。此外，我们认为这是环境的后果。 转移性乳腺癌微环境中富集的TGF-β浓度 骨中的细胞，并且可以通过抗TGF β治疗来减少，我们假设这将 促进成骨细胞分化，改善骨质量。 为了验证这一假设，我们计划研究TGF β在成骨细胞中的具体作用， 分化，患者和乳腺癌临床前模型的骨结构和质量 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TGF β信号传导在 通过使用TGF-β受体激酶有条件敲除的小鼠， 通过最先进的技术评估骨质量，包括拉曼光谱、原子能 力显微镜和uCT。在目标2中，我们将确定抗TGF β治疗的效果。 使用抗TGF-β抗体对骨质量的影响，与对肿瘤负荷的影响平行， 在携带人乳腺癌细胞的小鼠中的成骨细胞分化和骨结构， 指导目标3中的临床研究设计，并提供有关 从抗TGF β治疗中获益。在目标3中，我们将确定抗TGF β的作用。 在转移性乳腺癌患者的I期研究中，这些研究 关注乳腺癌的一个重要并发症，它显著影响 对晚期疾病患者的生活，并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.