Abstract
Metastasis remains the major obstacle to improved survival for breast cancer patients. Downregulation of FOXO3a transcription factor in breast cancer is causally associated with the development of metastasis through poorly understood mechanisms. Here, we report that FOXO3a is functionally related to the inhibition of VEGF-A/NRP1 signaling and to the consequent suppression of breast cancer metastasis. We show that FOXO3a directly induces miR-29b-2 and miR-338 expression. Ectopic expression of miR-29b-2/miR-338 significantly suppresses EMT, migration/invasion, and in vivo metastasis of breast cancer. Moreover, we demonstrate that miR-29b-2 directly targets VEGF-A while miR-338 directly targets NRP1, and show that regulation of miR-29b-2 and miR-338 mediates the ability of FOXO3a to suppress VEGF-A/NRP1 signaling and breast cancer metastasis. Clinically, our results show that the FOXO3a-miR-29b-2/miR-338-VEGF-A/NRP1 axis is dysregulated and plays a critical role in disease progression in breast cancer. Collectively, our findings propose that FOXO3a functions as a metastasis suppressor, and define a novel signaling axis of FOXO3a-miRNA-VEGF-A/NRP1 in breast cancer, which might be potential therapeutic targets for breast cancer.
Highlights
Breast cancer is the most common cancer diagnosed and the second leading cause of cancer-related deaths among women worldwide [1]
We found that the invasion ability of breast cancer cells was inversely correlated with FOXO3a expressions (Fig. 1A)
We found that overexpression of FOXO3a inhibited epithelial-to-mesenchymal transition (EMT) in breast cancer cells, which was evidenced by increased E-cadherin expression in conjunction with a concomitant decreased in the expression of mesenchymal markers vimentin and N-cadherin (Fig. 1E and Supplementary Fig. 2)
Summary
Breast cancer is the most common cancer diagnosed and the second leading cause of cancer-related deaths among women worldwide [1]. Neuropilin-1 (NRP1), a coreceptor of VEGF-A, forms complexes with VEGFRs to enhance the binding of VEGF-A to VEGFRs, promoting VEGF-A-mediated breast cancer cells EMT and metastasis [18,19,20]. No information is available as to whether microRNAs (miRNAs) play a role in the FOXO3amediated inhibition of VEGF-A/NRP1 signaling. Several reports focused on the interaction of miRNAs and FOXO3a and confirmed the involvement of miRNAs in the FOXO3a-mediated regulation of cancer progression and metastasis [7, 24], suggesting that FOXO3a might use miRNAs to make cell fate decisions. Our study suggests an important role of FOXO3a in inhibiting breast cancer metastasis and provides a previously undescribed mechanism of FOXO3a-mediated repression of VEGF-A/NRP1
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