Jornal de Patologia Clínica e Experimental

Abstrato

PIK3CA/AKT1 Mutations in Breast Carcinoma: a Comprehensive Review of Experimental and Clinical Studies

Megan L Troxell

The phosphatidylinositol-3-kinase (PI3K) pathway is an important nexus for integration of extracellular and intracellular signals, and there are very frequent perturbations of this pathway in breast cancer, making it an attractive target for therapeutic manipulation. Hotspot mutations in PIK3CA or AKT1 are found in nearly 30% of breast cancers, especially estrogen receptor-positive and Her-2/neu-positive subgroups. This review will emphasize experimental models, clinical characterization and implications of PIK3CA/AKT1 mutations in breast cancer. In vitro studies have demonstrated that these mutations are kinase-activating and can confer cellular transforming properties in the correct context. Further, overexpression of PIK3CA H1047R in a variety of murine models results in mammary proliferation and carcinomas, and established carcinomas may become PIK3CA H1047R-independent. Data from human breast carcinomas regarding the clinicopathologic significance of PIK3CA/AKT1 mutations were contradictory at first, yet trends are beginning to emerge. PIK3CA mutation seems to impart a favorable prognosis in estrogen-receptor positive breast cancers, and mutations are seen early, in pre-invasive breast lesions. Although larger studies are needed, PIK3CA mutations may not confer selective advantage in the metastatic setting. Numerous pharmacologic compounds targeting the PI3K pathway are in development. The complexity of PI3K crosstalk with other signaling cascades, negative feedback regulation, and the myriad of other genotypic and phenotypic deviations in breast cancers argues for thorough molecular characterization of tumors in cancer trials.