IQGAP1 - Clinical Significance

Clinical Significance

IQGAP1 is associated with cytoskeletal dynamics, transcription, cell adhesion, cell cycle, and morphology, all of which are disrupted in cancer. As a modulatory protein intersecting all of these pathways, IQGAP1 can couple many of them, and is also responsible for their proper propagation. Since cancer is a disease characterized by the perturbation of many of these cellular processes, IQGAP1 is a logical oncogene candidate and therapeutic target.

Expression analysis has implicated IQGAP1 in colorectal, squamous cell, breast, gastric, liver, lung, and ovarian cancers, and in some of these cancers, higher IQGAP1 expression levels indicate a poor prognosis.

In order for a cancer to metastasize, cells must gain migratory abilities and invade other tissues. Through Rac1/CDC42, IQGAP1 regulates cellular adhesion and actin dynamics.

In normal cells IQGAP1 localizes to areas of high actin turnover. This characteristic is echoed in invasive tissues, where IQGAP1 localizes to the leading edge of migrating cells. Over-expression of IQGAP1 was associated with increased migration and invasion in a human breast epithelial cancer cell line (MCF-7 cells). IQGAP1 may also be involved in the deregulation of proliferation and differentiation through its modulation of the ERK MAPK pathway.

IQGAP1 may be necessary for tumorigenesis. IQGAP1 knockdown in MCF-7 cancer cells reduced the malignant phenotype (serum-dependent proliferation and anchorage independent growth). 100% of mice injected with MCF-7 cells overexpressing IQGAP1 developed tumors and these tumors were highly invasive. Control MCF-7 cells formed tumors in 60% of the mice, and MCF-7 cells with stable knockdown of IQGAP1 only formed tumors 20% of the time. The mechanism for how IQGAP1 may modulate tumorigenesis/invasion through its various binding partners is of great interest.

IQGAP1 null mice appear significantly normal, with the only life history abnormality being an increase in gastric hyperplasia. Thus, IQGAP1 may be an effective therapeutic target, if its knockdown has little effect in homeostatic tissue but its expression is important in cancer.