The role of mutant KRAS and PIK3CA in human breast cancer tumorigenesis.

摘要

The development of individualized therapies for the treatment of breast cancer continues to evolve at a rapid pace. Recent genome wide efforts have uncovered new information regarding common genetic alterations that are present at high frequencies in human breast cancers. Among these, mutations in the gene encoding the p110alpha catalytic subunit of Pl3kinase, PIK3CA , are commonly present in breast cancers with a mutational frequency of approximately 25%. Importantly, three "hotspot" mutations compromise 80 to 90% of PIK3CA mutations allowing for rapid analysis of tumor samples to determine the mutational status of a patient's cancer.;The selective pressures leading to cancers with mutations in both KRAS and PIK3CA are unclear. This body of work demonstrates that somatic cell knock in of both KRAS G12V and oncogenic PIK3CA mutations in human breast epithelial cells results in synergistic activation of the PI3 Kinase and MAP Kinase pathways in vitro, and leads to tumor formation in immunocompromised mice. Importantly, xenografts from double knock in cells retain single copies of mutant KRAS and PIK3CA, akin to cancer cells with mutations in both KRAS and PIK3CA, suggesting that this synergism does not require increased copy number of either oncogene. This synergy is mediated by Ras/p110alpha binding, as inactivating point mutations within the Ras binding domain of PIK3CA significantly abate pathway signaling.;These results provide new insights into mutant KRAS function and its role in carcinogenesis. Furthermore, a discussion of the current views regarding the use of PIK3CA mutations as biomarkers for prognosis as well as predictors of response to therapies is provided. There are ongoing efforts to target mutant PIK3CA and the Pl3kinase pathway, and mutant PIK3CA status may be useful as a predictive marker of response to newer therapies in the future.