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

Abstract

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.

Impact Statement

Research on the bone metastatic vicious cycle frequently investigates how osteocytes and other cells involved in bone remodeling impact breast cancer cells, but the downstream impacts of the breast cancer cell response to the bone mechanical environment are understudied. This work is one of the few studies investigating how breast cancer cells respond to a bone-like fluid mechanical environment and will facilitate our understanding of the breast cancer bone metastatic vicious cycle. Additionally, to our knowledge, this is the first study that has examined how the timing of ionizing irradiation administration influences the breast cancer cell mechanoresponse in a 3D model. Mechanosensation and the cell mechanoresponse have largely been studied in 2D models, and an understanding of the physiologically relevant 3D environment is crucial to elucidating complex cell–extracellular matrix interactions and responses to damaging stimuli such as ionizing radiation.