Abstract
Simple SummaryAlthough 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.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.
Highlights
Metastasis remains hard to control and it is the greatest contributor to deaths from breast cancer [1]. cancer cells represent the main driving force of metastasis, the tumor microenvironment (TME)is indispensable in guiding metastatic behavior [2,3]
Given that adipocytes represent a dominant part of the breast cancer TME, it is rational to infer that adipocytes contribute to breast cancer progression and metastasis. 3T3-L1 preadipocytes were induced to develop into mature adipocytes, as confirmed by oil red O and BODIPY staining, and cocultured with breast cancer cells for 72 h (Figure 1A)
plasminogen activator inhibitor-1 (PAI-1) was confirmed as a new driver in adipocyte-driven metastatic behavior of breast cancer cells
Summary
Metastasis remains hard to control and it is the greatest contributor to deaths from breast cancer [1]. cancer cells represent the main driving force of metastasis, the tumor microenvironment (TME)is indispensable in guiding metastatic behavior [2,3]. Tumor cells interact closely with stromal cells by cytokine-mediated communication or direct cell-cell contact, which results in multiple signaling pathway crosstalk to potentiate the aggressiveness and metastasis of cancer cells [4]. The stromal cells in the breast cancer TME include cancer-associated fibroblasts (CAFs), mesenchymal stem cells, adipocytes, endothelial cells, pericytes and immune cells. Among these cells, the roles of CAFs and tumor-associated macrophages (TAMs) in breast cancer metastasis have been extensively investigated, and the focus has been on secreted factor-mediated interaction such as growth factors, inflammatory factors, integrins, proteases and chemokines [5,6,7,8,9,10,11,12,13]. Interest has extended to other cell types in the breast cancer TME, such as adipose stem cells (ASCs), cancer-associated adipocytes (CAAs) and adipocytes [14,15,16]
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