FoxM1 promotes breast tumorigenesis by activating PDGF-A and forming a positive feedback loop with the PDGF/AKT signaling pathway
Metrics: PDF 2063 views | HTML 3265 views | ?
Guanzhen Yu1,3,*, Aidong Zhou1,*, Jianfei Xue1, Chen Huang2, Xia Zhang3, Shin-Hyuk Kang1, Wen-Tai Chiu1, Christina Tan1, Keping Xie2,4, Jiejun Wang3 and Suyun Huang1,4
1 Departments of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
2 Departments of Gastroenterology, Hepatology, and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
3 Department of Medical Oncology, Changzheng Hospital, Shanghai, People’s Republic of China
4 Program in Cancer Biology, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX, USA
* These authors contributed equally to this work
Suyun Huang, email:
Keywords: breast cancer, FoxM1, PDGF-A, AKT, tumorigenesis
Received: November 19, 2014 Accepted: February 20, 2015 Published: March 14, 2015
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.
All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.