TGF-beta in the Bone Microenvironment: Role in Breast Cancer Metastases

Breast cancer is the most prevalent cancer among females worldwide. It has long been known that cancers preferentially metastasize to particular organs, and bone metastases occur in similar to 70% of patients with advanced breast cancer. Breast cancer bone metastases are predominantly osteolytic and accompanied by bone destruction, bone fractures, pain, and hypercalcemia, causing severe morbidity and hospitalization. In the bone matrix, transforming growth factor-beta (TGF-beta) is one of the most abundant growth factors, which is released in active form upon tumor-induced osteoclastic bone resorption. TGF-beta, in turn, stimulates bone metastatic cells to secrete factors that further drive osteolytic destruction of the bone adjacent to the tumor, categorizing TGF-beta as a crucial factor responsible for driving the feed-forward vicious cycle of cancer growth in bone. Moreover, TGF-beta activates epithelial-to-mesenchymal transition, increases tumor cell invasiveness and angiogenesis and induces immunosuppression. Blocking the TGF-beta signaling pathway to interrupt this vicious cycle between breast cancer and bone offers a promising target for therapeutic intervention to decrease skeletal metastasis. This review will describe the role of TGF-beta in breast cancer and bone metastasis, and pre-clinical and clinical data will be evaluated for the potential use of TGF-beta inhibitors in clinical practice to treat breast cancer bone metastases.