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

35 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 Jan 1
Externally publishedYes

Fingerprint

Platelet-Derived Growth Factor
Carcinogenesis
Breast
Breast Neoplasms
Up-Regulation
Cell Proliferation
Platelet-Derived Growth Factor Receptors
1-Phosphatidylinositol 4-Kinase
platelet-derived growth factor A
Binding Sites
Mutation
Growth

Keywords

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

ASJC Scopus subject areas

  • Oncology

Cite this

FoxM1 promotes breast tumorigenesis by activating PDGF-A and forming a positive feedback loop with the PDGF/AKT signaling pathway. / Yu, Guanzhen; Zhou, Aidong; Xue, Jianfei; Huang, Chen; Zhang, Xia; Kang, Shin-Hyuk; Chiu, Wen Tai; Tan, Christina; Xie, Keping; Wang, Jiejun; Huang, Suyun.

In: Oncotarget, Vol. 6, No. 13, 01.01.2015, p. 11281-11294.

Research output: Contribution to journalArticle

Yu, G, Zhou, A, Xue, J, Huang, C, Zhang, X, Kang, S-H, Chiu, WT, 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, vol. 6, no. 13, pp. 11281-11294. https://doi.org/10.18632/oncotarget.3596
Yu, Guanzhen ; Zhou, Aidong ; Xue, Jianfei ; Huang, Chen ; Zhang, Xia ; Kang, Shin-Hyuk ; Chiu, Wen Tai ; Tan, Christina ; Xie, Keping ; Wang, Jiejun ; Huang, Suyun. / FoxM1 promotes breast tumorigenesis by activating PDGF-A and forming a positive feedback loop with the PDGF/AKT signaling pathway. In: Oncotarget. 2015 ; Vol. 6, No. 13. pp. 11281-11294.
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