Abstract
Breast cancer is the most prevalent cancer among females worldwide leading to approximately 350,000 deaths each year. It has long been known that cancers preferentially metastasize to particular organs, and bone metastases occur in ~70% of patients with advanced breast cancer. Breast cancer bone metastases are predominantly osteolytic and accompanied by increased fracture risk, pain, nerve compression and hypercalcemia, causing severe morbidity. In the bone matrix, transforming growth factor-β (TGF-β) is one of the most abundant growth factors, which is released in active form upon tumor-induced osteoclastic bone resorption. TGF-β, in turn, stimulates bone metastatic tumor cells to secrete factors that further drive osteolytic bone destruction adjacent to the tumor. Thus, TGF-β is a crucial factor responsible for driving the feed-forward vicious cycle of cancer growth in bone. Moreover, TGF-β activates epithelial-to-mesenchymal transition, increases tumor cell invasiveness and angiogenesis and induces immunosuppression. Blocking the TGF-β 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-β in breast cancer and bone metastasis, and pre-clinical and clinical data will be evaluated for the potential use of TGF-β inhibitors in clinical practice to treat breast cancer bone metastases.
Highlights
Cancer is the leading cause of death in economically developed countries
It has long been known that cancers preferentially metastasize to particular organs, and bone metastases occur in ~70% of patients with advanced breast cancer
This review will describe the role of transforming growth factor-β (TGF-β) in breast cancer and bone metastasis, and pre-clinical and clinical data will be evaluated for the potential use of TGF-β inhibitors in clinical practice to treat breast cancer bone metastases
Summary
Cancer is the leading cause of death in economically developed countries. Breast cancer is the most frequently diagnosed cancer in females accounting for 23% (1.38 million) of the total new cancer cases and is the leading cause of cancer death among females worldwide, [1,2]. Patients with bone metastases are at risk of skeletal complications, including spinal cord compression, pain, pathological fracture, hypercalcemia, complications due to surgery to bone, and radiation therapy These comorbidities are known collectively as skeletal-related events (SREs). Over the past several years, several therapeutic strategies have been developed to inhibit TGFβ, including, TGF-β receptor kinase inhibitors, TGF-β neutralizing antibodies, soluble receptor decoys (Fc fusions) and TGF-β antisense oligonucleotides [12]. Many of these are in early-stage clinical trials for various disease indications with particular emphasis as potential cancer therapies, including bone metastases. We will focus on the role of TGF-β in breast cancer and bone metastasis and discuss the potential use of novel TGF-β inhibiting compounds and biologics in clinical practice to treat bone metastases
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