Role of TGF-<i>β</i> in breast cancer bone metastases

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.

Bone-Induced Expression of Integrin β3 Enables Targeted Nanotherapy of Breast Cancer Metastases

“…Bioactive TGF-β plays a critical role in both the homeostatic and pathologic bone microenvironment, regulating osteolytic destruction and pathologic muscle weakness (30,46). TGF-β has been shown to induce β3 expression on normal and transformed mammary epithelial cells (47-49), but the physiological regulation of tumoral β3 in vivo has not been explored.…”

Bilateral breast keloids in an elderly woman associated with bilateral breast cancers and high concentration of serum tumor growth factor‐β

“…One is that the source of TGF‐β1 is not breast keloid skin. In this case, breast cancer and/or bones to which breast cancer had metastasized represent possible sources of TGF‐β1 . The other explanation is that expression levels of TGF‐β1 were too low to detect.…”

Transcriptional regulation of tenascin‐W by TGF‐beta signaling in the bone metastatic niche of breast cancer cells

“…It is known that upon stimulation of osteoblasts by cytokines released by the tumor cells, osteoblasts release RANKL which in turn promotes differentiation and activation of osteoclasts. Activated osteoclasts resorb the bone matrix with the consequent release of cytokines including TGFβ . These cytokines will act back on the osteoblasts as well as the tumor cells and in a vicious cycle keep the osteolytic lesions growing.…”

“…These cytokines will act back on the osteoblasts as well as the tumor cells and in a vicious cycle keep the osteolytic lesions growing. Because of these findings, inhibition of osteoclasts by bisphosphonates as well as RANKL and TGFβ‐targeting agents are presently tested as adjuvant therapy for the treatment of breast cancer patients with bone metastases . The benefit of such treatments may include reduced TNW expression in the microenvironment of the metastatic cells and alleviate the tumor‐promoting effects exerted by TNW.…”

“…Activated osteoclasts resorb the bone matrix with the consequent release of cytokines including TGFb. 32 These cytokines will act back on the osteoblasts as well as the tumor cells and in a vicious cycle keep the osteolytic lesions growing. Because of these findings, inhibition of osteoclasts by bisphosphonates as well as RANKL and TGFb-targeting agents are presently tested as adjuvant therapy for the treatment of breast cancer patients with bone metastases.…”