Transforming growth factor-β1 is the predominant isoform required for breast cancer cell outgrowth in bone

Transforming growth factor (TGF)-β signaling is a potent modulator of the invasive and metastatic behavior of breast cancer cells. Indeed, breast tumor responsiveness to TGF-β is important for the development of osteolytic bone metastases. However, the specific TGF-β isoforms that promote breast cancer outgrowth in bone is unknown. We demonstrate that expression of a TGF-β ligand trap, which neutralizes TGF-β1 and TGF-β3, in MDA-MB-231 breast cancer cells diminished their outgrowth in bone and reduced the severity of osteolytic lesion formation when compared with controls. We further show that a reduction or loss of TGF-β1 expression within the bone microenvironment of TGF-β1+/− and TGF-β1−/− mice significantly reduced the incidence of breast tumor outgrowth compared with wild-type animals. Interestingly, those tumors capable of growing within the tibiae of TGF-β1-deficient mice had upregulated expression of all three TGF-β isoforms. Finally, breast cancer cells expressing the TGF-β ligand trap showed a pronounced reduction in their ability to form osteolytic lesions when injected into the tibiae of TGF-β1+/− mice. Thus, our studies show that both host- and tumor-derived TGF-β expression plays a critical role during the establishment and outgrowth of breast cancer cells in bone.