TRAF4 and membrane lipids orchestrate cancer cell migration
In this mammary gland section, the colocalization between TRAF4 (green) and tight junctions (red) appears yellow and exhibits a typical honeycomb pattern at the top of epithelial cells whose nuclei are labeled in blue. © Cancers
Dec. 3, 2013
Marie-Christine RIO and Catherine-Laure TOMASETTO’s team at the IGBMC reveals the involvement of TRAF4 in the progression of breast cancer and identifies a new partner of the protein which allows it to be sent to tight junctions in mammary gland cells. These results are published on December 3rd in PLOS Biology.
With up to 50,000 new cases diagnosed in France in 2012, breast cancer is the most common cancer in women. Most of them affect mammary gland cells which are termed epithelial. These cells are oriented in space; the cell membrane on the top of the cell having different properties compared to the ones on its sides or bottom. A specialized cellular structure named a tight junction borders the top from the bottom and side membrane. In addition to making a hermetic barrier, tight junctions maintain the adhesion between cells. These boundaries which are essential for preserving the integrity of epithelial tissues are often disrupted in cancer cells.
TRAF4 is a protein localized at tight junctions in all epithelial cells and in particular in the mammary gland. It belongs to a family of 7 proteins whose members regulate immunity and inflammation. Unlike other proteins of this family, TRAF4 is frequently overexpressed in breast cancers, but its function and specific role at tight junctions were previously unknown. In a new collaborative study, Marie-Christine RIO and Catherine-Laure TOMASETTO’s team at the IGBMC reveals the involvement of TRAF4 in the progression of breast cancer and identifies the molecular partner which targets it to tight junctions.
The researchers show that TRAF4 is routed to tight junctions through an interaction with membrane lipids named phosphoinositides. They reveal for the first time that all TRAF proteins bind these membrane lipids. The researchers showed that excessive amount of TRAF4 as it is the case in cancer cells weakens tight junctions and ultimately favors a loss of contact between cells, two properties used by cancer cells to migrate and colonize other areas of the body.
This study reveals an unknown property of the TRAF protein family; the ability to bind membrane lipids. It also highlights how excessive amount of TRAF4 might favor the progression of breast cancer. By destabilizing tight junctions in epithelial cells of the mammary gland, it promotes cell migration and thus potentially enhances metastasis formation. This result also opens novel perspectives; TRAF4 could indeed be an interesting therapeutic target to limit the progression of breast cancer.