FoxM1 promotes breast tumorigenesis by activating PDGF-A and forming a positive feedback loop with the PDGF/AKT signaling pathway.

Guanzhen Yu,Aidong Zhou,Christina Tan,Jiejun Wang,Keping Xie,Shin-Hyuk Kang,Jianfei Xue,Xia Zhang,Chen Huang,Suyun Huang,Wen-Tai Chiu

doi:10.18632/oncotarget.3596

Guanzhen Yu, Aidong Zhou + Show 9 more

Open Access

https://doi.org/10.18632/oncotarget.3596

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Abstract

The autocrine platelet-derived growth factor (PDGF)/PDGF receptor (PDGFR) signaling pathway promotes breast cancer tumorigenesis, but the mechanisms for its dysregulation in breast cancer are largely unknown. In the study, we identified PDGF-A as a novel transcriptional target of FoxM1. FoxM1 directly binds to two sites in the promoter of PDGF-A and activates its transcription. Mutation of these FoxM1-binding sites diminished PDGF-A promoter activity. Increased FoxM1 resulted in the upregulation of PDGF-A, which led to activation of the AKT pathway and increased breast cancer cell proliferation and tumorigenesis, whereas knockdown of FoxM1 does the opposite. Blocking AKT activation with a phosphoinositide 3-kinase/AKT inhibitor decreased FoxM1-induced cell proliferation. Moreover, PDGF/AKT pathway upregulates the expression of FoxM1 in breast cancer cells. Knockdown of PDGF-A or blockade of AKT activation inhibited the expression of FoxM1 in breast cancer cells. Furthermore, expression of FoxM1 significantly correlated with the expression of PDGF-A and the activated AKT signaling pathway in human breast cancer specimens. Our study demonstrates a novel positive regulatory feedback loop between FoxM1 and the PDGF/AKT signaling pathway; this loop contributes to breast cancer cell growth and tumorigenesis.

Highlights

Breast cancer is the most common malignancy and the leading cause of cancer-related death in women worldwide [1]
We showed that FoxM1 enhances the survival and growth of human breast cancer cells through the platelet-derived growth factor (PDGF)/AKT signaling pathway
FoxM1 stimulates the transcription of PDGF-A by directly binding to its promoter at two sites, which in turn leads to the activation of the AKT pathway, one of the most important pathways underlying breast tumorigenesis

Summary

Introduction

Breast cancer is the most common malignancy and the leading cause of cancer-related death in women worldwide [1]. Understanding the molecular mechanisms of the development and progression of breast cancer will highlight strategies for accurate diagnosis, early intervention, and effective therapies. Several pathways have been implicated in breast cancer, including p53, epidermal growth factor receptor (EGFR), PDGF/PDGFR, PI3K/AKT, and mammalian target of rapamycin (mTOR) [2]. The AKT pathway is strongly activated during breast cancer development and progression. Studies have shown that phosphorylation and activation of AKT kinase is often achieved by stimulation of the PDGF pathway through the binding of PDGFs to PDGFRs [4]. The activated PDGF pathway has been shown to prevent cancer cells from undergoing apoptosis during epithelialmesenchymal transition and to promote breast cancer progression and metastasis [5, 6]

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