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 Mills

Research output: Contribution to journalArticle

267 Citations (Scopus)

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
Externally publishedYes

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PTEN Phosphohydrolase
Phosphatidylinositol 3-Kinase
Protein Stability
Endometrial Neoplasms
Mutation
Neoplasms
Neoplasm Genes

ASJC Scopus subject areas

  • Oncology

Cite this

High frequency of PIK3R1 and PIK3R2 mutations in endometrial cancer elucidates a novel mechanism for regulation of PTEN protein stability. / Cheung, Lydia W.T.; Hennessy, Bryan T.; Li, Jie; Yu, Shuangxing; Myers, Andrea P.; Djordjevic, Bojana; Lu, Yiling; Katherine, Stemke Hale; Dyer, Mary D.; Zhang, Fan; Ju, Zhenlin; Cantley, Lewis C.; Scherer, Steven E.; Liang, Han; Lu, Karen H.; Broaddus, Russell R.; Mills, Gordon.

In: Cancer Discovery, Vol. 1, No. 2, 07.06.2011, p. 170-185.

Research output: Contribution to journalArticle

Cheung, LWT, Hennessy, BT, Li, J, Yu, S, Myers, AP, Djordjevic, B, Lu, Y, Katherine, SH, Dyer, MD, Zhang, F, Ju, Z, Cantley, LC, Scherer, SE, Liang, H, Lu, KH, Broaddus, RR & Mills, G 2011, 'High frequency of PIK3R1 and PIK3R2 mutations in endometrial cancer elucidates a novel mechanism for regulation of PTEN protein stability', Cancer Discovery, vol. 1, no. 2, pp. 170-185. https://doi.org/10.1158/2159-8290.CD-11-0039
Cheung, Lydia W.T. ; Hennessy, Bryan T. ; Li, Jie ; Yu, Shuangxing ; Myers, Andrea P. ; Djordjevic, Bojana ; Lu, Yiling ; Katherine, Stemke Hale ; Dyer, Mary D. ; Zhang, Fan ; Ju, Zhenlin ; Cantley, Lewis C. ; Scherer, Steven E. ; Liang, Han ; Lu, Karen H. ; Broaddus, Russell R. ; Mills, Gordon. / High frequency of PIK3R1 and PIK3R2 mutations in endometrial cancer elucidates a novel mechanism for regulation of PTEN protein stability. In: Cancer Discovery. 2011 ; Vol. 1, No. 2. pp. 170-185.
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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.",
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AU - Cheung, Lydia W.T.

AU - Hennessy, Bryan T.

AU - Li, Jie

AU - Yu, Shuangxing

AU - Myers, Andrea P.

AU - Djordjevic, Bojana

AU - Lu, Yiling

AU - Katherine, Stemke Hale

AU - Dyer, Mary D.

AU - Zhang, Fan

AU - Ju, Zhenlin

AU - Cantley, Lewis C.

AU - Scherer, Steven E.

AU - Liang, Han

AU - Lu, Karen H.

AU - Broaddus, Russell R.

AU - Mills, Gordon

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