The EGFR-GEP100-Arf6-AMAP1 signaling pathway specific to breast cancer invasion and metastasis

Hisataka Sabe, Shigeru Hashimoto, Masaki Morishige, Eiji Ogawa, Ari Hashimoto, Jin Min Nam, Koichi Miura, Hajime Yano, Yasuhito Onodera

Research output: Contribution to journalReview articlepeer-review

94 Citations (Scopus)


Tumors are tissue-specific diseases, and their mechanisms of invasion and metastasis are highly diverse. In breast cancer, biomarkers that specifically correlate with the invasive phenotypes have not been clearly identified. A small GTPase Arf6 primarily regulates recycling of plasma membrane components. We have shown that Arf6 and its effector AMAP1 (DDEF1, DEF1, ASAP1 and centaurin β4) are abnormally overexpressed in some breast cancers and used for their invasion and metastasis. Overexpression of these proteins is independent of the transcriptional upregulation of their genes, and occurs only in highly malignant breast cancer cells. We recently identified GEP100 (BRAG2) to be responsible for the Arf6 activation to induce invasion and metastasis, by directly binding to ligand-activated epidermal growth factor receptor (EGFR). A series of our studies revealed that for activation of the invasion pathway of EGFR, it is prerequisite that Arf6 and AMAP1 both are highly overexpressed, and that EGFR is activated by ligands. Pathological analyses indicate that a significant large population of human ductal cancers may utilize the EGFR-GEP100-Arf6-AMAP1 pathway for their malignancy. Microenvironments have been highly implicated in the malignancy of mammary tumors. Our results reveal an aspect of the precise molecular mechanisms of some breast cancers, in which full invasiveness is not acquired just by intracellular alterations of cancer cells, but extracellular factors from microenvironments may also be necessary. Possible translation of our knowledge to cancer therapeutics will also be discussed.

Original languageEnglish
Pages (from-to)982-993
Number of pages12
Issue number8
Publication statusPublished - 2009
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Structural Biology
  • Biochemistry
  • Molecular Biology
  • Genetics
  • Cell Biology


Dive into the research topics of 'The EGFR-GEP100-Arf6-AMAP1 signaling pathway specific to breast cancer invasion and metastasis'. Together they form a unique fingerprint.

Cite this