Radiation Modulates the Mechanoresponse of Bone-Homing Triple-Negative Breast Cancer Cells

Bone is a common site of breast cancer metastasis, which dramatically increases fracture risk. Recent in vivo bone metastasis studies show that mechanical loading is osteoprotective; however, little is known about how loading regulates breast cancer cell function in the unique bone mechanical environment, especially in combination with radiotherapy, one of the first-line treatments for advanced breast cancer patients. Here, we characterize the breast cancer cell response to a range of bone-mimicking fluid shears and determine how irradiation further modulates one candidate gene: SERPINE1. We found that irradiation, regardless of dosage, modulates SERPINE1 expression and is sensitive to the timing of administration. Additionally, protein expression of SERPINE1 accompanies a protumorigenic gene expression profile, which is elevated with higher-magnitude fluid shear stresses in a bone-mimicking 3D environment. Thus, we postulate that plasminogen activator inhibitor-1 (PAI-1) (encoded by SERPINE1) is a critical growth factor contributing to osteolytic lesion development in the bone metastatic vicious cycle of breast cancer.