Metastasis-associated wound repair promotes reciprocal lung epithelium activation and breast cancer metastatic outgrowth

AT2-derived secreted factors also promote triple-negative breast cancer (TNBC) growth. AT2 secreted factors are regulated by the cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB). Targeting CREB signaling with the phosphodiesterase 4 (PDE4) inhibitor roflumilast reduced AT2-BC reciprocal interactions in vitro and metastatic outgrowth in vivo.

Finally, AT2 cells adjacent to metastases in lungs from patients with metastatic BC express higher PDE4B compared to AT2 cells in normal lungs. Alveolar epithelial cells are the most common cell type in the lung. Our studies demonstrate the potential for targeting metastasis-associated wound repair and lung epithelial cell activation during metastatic outgrowth with FDA-approved PDE4 inhibitors.

This strategy may be an effective way to treat and manage progression of established metastatic BC within the lung.