High frequency of PIK3R1 and PIK3R2 mutations in endometrial cancer elucidates a novel mechanism for regulation of PTEN protein stability

Lydia W.T. Cheung, Bryan T. Hennessy, Jie Li, Shuangxing Yu, Andrea P. Myers, Bojana Djordjevic, Yiling Lu, Stemke Hale Katherine, Mary D. Dyer, Fan Zhang, Zhenlin Ju, Lewis C. Cantley, Steven E. Scherer, Han Liang, Karen H. Lu, Russell R. Broaddus, Gordon B. Mills

    Research output: Contribution to journalArticle

    280 Scopus citations

    Abstract

    We demonstrate that phosphatidylinositol 3-kinase (PI3K) pathway aberrations occur in.80% of endometrioid endometrial cancers, with coordinate mutations of multiple PI3K pathway members being more common than predicted by chance. PIK3R1 (p85α) mutations occur at a higher rate in endometrial cancer than in any other tumor lineage, and PIK3R2 (p85β), not previously demonstrated to be a cancer gene, is also frequently mutated. The dominant activation event in the PI3K pathway appears to be PTEN protein loss. However, in tumors with retained PTEN protein, PI3K pathway mutations phenocopy PTEN loss, resulting in pathway activation. KRAS mutations are common in endometrioid tumors activating independent events from PI3K pathway aberrations. Multiple PIK3R1 and PIK3R2 mutations demonstrate gain of function, including disruption of a novel mechanism of pathway regulation wherein p85α dimers bind and stabilize PTEN. Taken together, the PI3K pathway represents a critical driver of endometrial cancer pathogenesis and a novel therapeutic target. siGNiFicaNce: Our data indicate that the PI3K pathway is targeted in the vast majority of endometrioid endometrial cancers leading to PI3K pathway activation. Frequent oncogenic mutations in PIK3R1 and PIK3R2 provide evidence for their role in endometrial cancer pathophysiology with patient-specific mutations revealing a novel mechanism by which p85α regulates the PI3K pathway through stabilizing PTEN.

    Original languageEnglish (US)
    Pages (from-to)170-185
    Number of pages16
    JournalCancer discovery
    Volume1
    Issue number2
    DOIs
    StatePublished - Jun 7 2011

    ASJC Scopus subject areas

    • Oncology

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  • Cite this

    Cheung, L. W. T., Hennessy, B. T., Li, J., Yu, S., Myers, A. P., Djordjevic, B., Lu, Y., Katherine, S. H., Dyer, M. D., Zhang, F., Ju, Z., Cantley, L. C., Scherer, S. E., Liang, H., Lu, K. H., Broaddus, R. R., & Mills, G. B. (2011). High frequency of PIK3R1 and PIK3R2 mutations in endometrial cancer elucidates a novel mechanism for regulation of PTEN protein stability. Cancer discovery, 1(2), 170-185. https://doi.org/10.1158/2159-8290.CD-11-0039