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-B concentrations which are enriched in the microenvironment of metastatic breast cancer cells in bone, and can be decreased by anti-TGFB 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 TGFB 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 TGFB signaling in osteoblasts by the use of mice with conditional knockout of the TGF-B 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-TGFB 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-TGFB therapy. In Aim 3, we will determine the effects of anti-TGFB 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.