Synaptojanin 2 is a druggable mediator of metastasis and the gene is overexpressed and amplified in breast cancer.

Abstract

Amplified HER2, which encodes a member of the epidermal growth factor receptor (EGFR) family, is a target of effective therapies against breast cancer. In search for similarly targetable genomic aberrations, we identified copy number gains in SYNJ2, which encodes the 5'-inositol lipid phosphatase synaptojanin 2, as well as overexpression in a small fraction of human breast tumors. Copy gain and overexpression correlated with shorter patient survival and a low abundance of the tumor suppressor microRNA miR-31. SYNJ2 promoted cell migration and invasion in culture and lung metastasis of breast tumor xenografts in mice. Knocking down SYNJ2 impaired the endocytic recycling of EGFR and the formation of cellular lamellipodia and invadopodia. Screening compound libraries identified SYNJ2-specific inhibitors that prevented cell migration but did not affect the related neural protein SYNJ1, suggesting that SYNJ2 is a potentially druggable target to block cancer cell migration.

• Authors: Nir Ben-Chetrit, David Chetrit, Roslin Russell, Cindy Körner, Maicol Mancini, Ali Abdul-Hai, Tomer Itkin, Silvia Carvalho, Hadas Cohen-Dvashi, Wolfgang J Koestler, Kirti Shukla, Moshit Lindzen, Merav Kedmi, Mattia Lauriola, Ziv Shulman, Haim Barr, Dalia Seger, Daniela A Ferraro, Fresia Pareja, Hava Gil-Henn, Tsvee Lapidot, Ronen Alon, Fernanda Milanezi, Marc Symons, Rotem Ben-Hamo, Sol Efroni, Fernando Schmitt, Stefan Wiemann, Carlos Caldas, Marcelo Ehrlich, Yosef Yarden
• Journal: Science signaling (Sci Signal) Vol. 8 Issue 360 Pg. ra7 (Jan 20 2015) ISSN: 1937-9145 [Electronic] United States
• PMID: 25605973 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015, American Association for the Advancement of Science.

Chemical References

• RNA, Small Interfering
• ErbB Receptors
• Phosphoric Monoester Hydrolases
• phosphoinositide 5-phosphatase

Topics

• Animals
• Breast Neoplasms (drug therapy, genetics, metabolism, physiopathology)
• Cell Line, Tumor
• Cell Movement (drug effects)
• Drug Discovery
• ErbB Receptors (metabolism)
• Female
• Fluorescent Antibody Technique
• Gene Dosage
• Gene Expression Regulation, Neoplastic (genetics)
• Humans
• Image Processing, Computer-Assisted
• Immunoblotting
• Immunohistochemistry
• Mice
• Mice, SCID
• Microscopy, Electron, Scanning
• Neoplasm Metastasis (genetics)
• Phosphoric Monoester Hydrolases (antagonists & inhibitors, genetics, metabolism)
• Podosomes (genetics, physiology)
• Pseudopodia (genetics, physiology)
• RNA, Small Interfering (genetics)
• Statistics, Nonparametric