File Download

There are no files associated with this item.

  Links for fulltext
     (May Require Subscription)

Conference Paper: Mutation and functional analysis of PIK3CA and PIK3R1 in endometrial cancer

TitleMutation and functional analysis of PIK3CA and PIK3R1 in endometrial cancer
Authors
Issue Date2011
PublisherAmerican Association for Cancer Research. The Journal's web site is located at http://cancerres.aacrjournals.org/
Citation
The 102nd Annual Meeting of the American Association for Cancer Research (AACR 2011), Orlando, FL., 2-6 April 2011. In Cancer Research, 2011, v. 71 n. 8 suppl., abstract no. LB-247 How to Cite?
AbstractThe phosphatidylinositol 3 kinase (PI3K) pathway is the most frequently activated pathway across multiple tumor lineages and this is a potential therapeutic target. As a critical step to accelerate therapeutic development in endometrial cancer, we performed a comprehensive analysis of mutation and function of PI3K pathway members in a set of 243 highly characterized endometrial tumors. Whole gene resequencing revealed the highest frequencies of mutation in the PI3K pathway of any tumor lineage including PTEN (44%), PIK3CA (40%; encoding the p110α catalytic subunit of PI3K) and PIK3R1 (20%; encoding the p85a regulatory subunit). Indeed, when complete protein loss is considered, almost 80% of endometrioid endometrial cancers demonstrate an aberration in the PI3K pathway. Remarkably, mutations in the PI3K pathway were not mutually exclusive and indeed co-existence of PIK3CA or PIK3R1 mutation with heterozygous PTEN mutation occurred at frequencies higher than predicted by the frequency of each lesion alone. High-throughput reverse-phase protein array suggested that the dominant signaling effects occurred with PTEN protein loss and that PIK3CA or PIK3R1 mutation functionally mimic PTEN protein loss as indicated by protein markers including phosphorylated Akt and stathmin. Thus it appears likely that co-mutations in the PI3K pathway are selected to compensate haploinsufficiency of PTEN due to PTEN heterozygous mutation. To determine the functional consequences of mutations in PIK3R1, we demonstrated that several somatic PIK3R1 mutations tested conferred cytokine-independent growth on interleukin-3-dependent Ba/F3 cells and induced Akt phosphorylation in endometrial cancer cell lines indicating that they were gain of function mutations likely acting as oncogenes. Strikingly two of the gain of function mutations (E160* and R348*) lacked the ability to bind to the p110 catalytic subunit and E160* failed to bind to both p110 and PTEN. We demonstrate that E160* disrupts a novel mechanism of pathway regulation wherein p85 binds and stabilizes PTEN. Together, the data indicate that the PI3K pathway is targeted in the vast majority of endometrioid endometrial cancers representing a novel opportunity for implementation of targeted therapy.
Persistent Identifierhttp://hdl.handle.net/10722/225138
ISSN
2015 Impact Factor: 8.556
2015 SCImago Journal Rankings: 5.372

 

DC FieldValueLanguage
dc.contributor.authorCheung, WTL-
dc.contributor.authorHennessy, BT-
dc.contributor.authorLi, J-
dc.contributor.authorYu, SX-
dc.contributor.authorMyers, AP-
dc.contributor.authorDjordjevic, B-
dc.contributor.authorLu, Y-
dc.contributor.authorStemke-Hale, K-
dc.contributor.authorZhang, F-
dc.contributor.authorJu, Z-
dc.contributor.authorCantley, LC-
dc.contributor.authorScherer, SE-
dc.contributor.authorLiang, H-
dc.contributor.authorLu, KH-
dc.contributor.authorRussell, BR-
dc.contributor.authorMills, GB-
dc.date.accessioned2016-04-22T06:11:18Z-
dc.date.available2016-04-22T06:11:18Z-
dc.date.issued2011-
dc.identifier.citationThe 102nd Annual Meeting of the American Association for Cancer Research (AACR 2011), Orlando, FL., 2-6 April 2011. In Cancer Research, 2011, v. 71 n. 8 suppl., abstract no. LB-247-
dc.identifier.issn0008-5472-
dc.identifier.urihttp://hdl.handle.net/10722/225138-
dc.description.abstractThe phosphatidylinositol 3 kinase (PI3K) pathway is the most frequently activated pathway across multiple tumor lineages and this is a potential therapeutic target. As a critical step to accelerate therapeutic development in endometrial cancer, we performed a comprehensive analysis of mutation and function of PI3K pathway members in a set of 243 highly characterized endometrial tumors. Whole gene resequencing revealed the highest frequencies of mutation in the PI3K pathway of any tumor lineage including PTEN (44%), PIK3CA (40%; encoding the p110α catalytic subunit of PI3K) and PIK3R1 (20%; encoding the p85a regulatory subunit). Indeed, when complete protein loss is considered, almost 80% of endometrioid endometrial cancers demonstrate an aberration in the PI3K pathway. Remarkably, mutations in the PI3K pathway were not mutually exclusive and indeed co-existence of PIK3CA or PIK3R1 mutation with heterozygous PTEN mutation occurred at frequencies higher than predicted by the frequency of each lesion alone. High-throughput reverse-phase protein array suggested that the dominant signaling effects occurred with PTEN protein loss and that PIK3CA or PIK3R1 mutation functionally mimic PTEN protein loss as indicated by protein markers including phosphorylated Akt and stathmin. Thus it appears likely that co-mutations in the PI3K pathway are selected to compensate haploinsufficiency of PTEN due to PTEN heterozygous mutation. To determine the functional consequences of mutations in PIK3R1, we demonstrated that several somatic PIK3R1 mutations tested conferred cytokine-independent growth on interleukin-3-dependent Ba/F3 cells and induced Akt phosphorylation in endometrial cancer cell lines indicating that they were gain of function mutations likely acting as oncogenes. Strikingly two of the gain of function mutations (E160* and R348*) lacked the ability to bind to the p110 catalytic subunit and E160* failed to bind to both p110 and PTEN. We demonstrate that E160* disrupts a novel mechanism of pathway regulation wherein p85 binds and stabilizes PTEN. Together, the data indicate that the PI3K pathway is targeted in the vast majority of endometrioid endometrial cancers representing a novel opportunity for implementation of targeted therapy.-
dc.languageeng-
dc.publisherAmerican Association for Cancer Research. The Journal's web site is located at http://cancerres.aacrjournals.org/-
dc.relation.ispartofCancer Research-
dc.titleMutation and functional analysis of PIK3CA and PIK3R1 in endometrial cancer-
dc.typeConference_Paper-
dc.identifier.emailCheung, WTL: lydiacwt@hku.hk-
dc.identifier.authorityCheung, WTL=rp02137-
dc.identifier.doi10.1158/1538-7445.AM2011-LB-247-
dc.identifier.volume71-
dc.identifier.issue8 suppl.-
dc.publisher.placeUnited States-

Export via OAI-PMH Interface in XML Formats


OR


Export to Other Non-XML Formats