Adipocyte-Derived Leptin Promotes PAI-1-Mediated Breast Cancer Metastasis in a STAT3/miR-34a Dependent Manner

SIMPLE SUMMARY: Although adipocytes affect the metastatic behavior of cancer cells, the underlying molecular mechanisms remain largely elusive. Thereby, we sought to screen for the signaling pathways responsible for adipocyte-induced motility of breast cancer cells by employing a breast cancer cell/adipocyte coculture system. Our study revealed that adipocyte coculture stimulated PAI-1 expression in breast cancer cells to potentiate cell motility. Furthermore, we obtained evidence that adipocytes secreted leptin to activate OBR in breast cancer cells, which phosphorylated STAT3 to promote the transcription of PAI-1 and repress the expression of miR-34a as the negative regulator of PAI-1. Our study provides new evidence for the involvement of adipocytes in breast cancer evolution, which advances the evolving roles of stromal cells in tumor pathogenesis. ABSTRACT: The crosstalk between cancer cells and adipocytes is critical for breast cancer progression. However, the molecular mechanisms underlying these interactions have not been fully characterized. In the present study, plasminogen activator inhibitor-1 (PAI-1) was found to be a critical effector of the metastatic behavior of breast cancer cells upon adipocyte coculture. Loss-of-function studies indicated that silencing PAI-1 suppressed cancer cell migration. Furthermore, we found that PAI-1 was closely related to the epithelial-mesenchymal transition (EMT) process in breast cancer patients. A loss-of-function study and a mammary orthotopic implantation metastasis model showed that PAI-1 promoted breast cancer metastasis by affecting the EMT process. In addition, we revealed that leptin/OBR mediated the regulation of PAI-1 through the interactions between adipocytes and breast cancer cells. Mechanistically, we elucidated that leptin/OBR further activated STAT3 to promote PAI-1 expression via miR-34a–dependent and miR-34a–independent mechanisms in breast cancer cells. In conclusion, our study suggests that targeting PAI-1 and interfering with its upstream regulators may benefit breast cancer patients.