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

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

Research output: Contribution to journalArticle

41 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)11281-11294
Number of pages14
JournalOncotarget
Volume6
Issue number13
DOIs
Publication statusPublished - 2015

Keywords

  • AKT
  • Breast cancer
  • FoxM1
  • PDGF-A
  • Tumorigenesis

ASJC Scopus subject areas

  • Oncology

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  • Cite this

    Yu, G., Zhou, A., Xue, J., Huang, C., Zhang, X., Kang, S. H., Chiu, W. T., Tan, C., Xie, K., Wang, J., & Huang, S. (2015). FoxM1 promotes breast tumorigenesis by activating PDGF-A and forming a positive feedback loop with the PDGF/AKT signaling pathway. Oncotarget, 6(13), 11281-11294. https://doi.org/10.18632/oncotarget.3596