Atypical PKCι contributes to poor prognosis through loss of apical-basal polarity and Cyclin E overexpression in ovarian cancer

Astrid M. Eder, Xiaomei Sui, Daniel G. Rosen, Laura K. Nolden, Kwai Wa Cheng, John P. Lahad, Madhuri Kango-Singh, Karen H. Lu, Carla L. Warneke, Edward M. Atkinson, Isabelle Bedrosian, Khandan Keyomarsi, Wen Lin Kuo, Joe Gray, Jerry C P Yin, Jinsong Liu, Georg Halder, Gordon Mills

Research output: Contribution to journalArticle

186 Citations (Scopus)

Abstract

We show that atypical PKCι, which plays a critical role in the establishment and maintenance of epithelial cell polarity, is genomically amplified and overexpressed in serous epithelial ovarian cancers. Furthermore, PKCι protein is markedly increased or mislocalized in all serous ovarian cancers. An increased PKCι DNA copy number is associated with decreased progression-free survival in serous epithelial ovarian cancers. In a Drosophila in vivo epithelial tissue model, overexpression of persistently active atypical PKC results in defects in apical-basal polarity, increased Cyclin E protein expression, and increased proliferation. Similar to the Drosophila model, increased PKCι proteins levels are associated with increased Cyclin E protein expression and proliferation in ovarian cancers. In nonserous ovarian cancers, increased PKCι protein levels, particularly in the presence of Cyclin E, are associated with markedly decreased overall survival. These results implicate PKCι as a potential oncogene in ovarian cancer regulating epithelial cell polarity and proliferation and suggest that PKCι is a novel target for therapy.

Original languageEnglish (US)
Pages (from-to)12519-12524
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number35
DOIs
StatePublished - Aug 30 2005
Externally publishedYes

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Cyclin E
Ovarian Neoplasms
Cell Polarity
Proteins
Drosophila
Epithelial Cells
Oncogenes
Disease-Free Survival
Epithelium
Maintenance
Cell Proliferation
DNA

Keywords

  • Epithelial cell polarity
  • Proliferation

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Atypical PKCι contributes to poor prognosis through loss of apical-basal polarity and Cyclin E overexpression in ovarian cancer. / Eder, Astrid M.; Sui, Xiaomei; Rosen, Daniel G.; Nolden, Laura K.; Cheng, Kwai Wa; Lahad, John P.; Kango-Singh, Madhuri; Lu, Karen H.; Warneke, Carla L.; Atkinson, Edward M.; Bedrosian, Isabelle; Keyomarsi, Khandan; Kuo, Wen Lin; Gray, Joe; Yin, Jerry C P; Liu, Jinsong; Halder, Georg; Mills, Gordon.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 102, No. 35, 30.08.2005, p. 12519-12524.

Research output: Contribution to journalArticle

Eder, AM, Sui, X, Rosen, DG, Nolden, LK, Cheng, KW, Lahad, JP, Kango-Singh, M, Lu, KH, Warneke, CL, Atkinson, EM, Bedrosian, I, Keyomarsi, K, Kuo, WL, Gray, J, Yin, JCP, Liu, J, Halder, G & Mills, G 2005, 'Atypical PKCι contributes to poor prognosis through loss of apical-basal polarity and Cyclin E overexpression in ovarian cancer', Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 35, pp. 12519-12524. https://doi.org/10.1073/pnas.0505641102
Eder, Astrid M. ; Sui, Xiaomei ; Rosen, Daniel G. ; Nolden, Laura K. ; Cheng, Kwai Wa ; Lahad, John P. ; Kango-Singh, Madhuri ; Lu, Karen H. ; Warneke, Carla L. ; Atkinson, Edward M. ; Bedrosian, Isabelle ; Keyomarsi, Khandan ; Kuo, Wen Lin ; Gray, Joe ; Yin, Jerry C P ; Liu, Jinsong ; Halder, Georg ; Mills, Gordon. / Atypical PKCι contributes to poor prognosis through loss of apical-basal polarity and Cyclin E overexpression in ovarian cancer. In: Proceedings of the National Academy of Sciences of the United States of America. 2005 ; Vol. 102, No. 35. pp. 12519-12524.
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AU - Atkinson, Edward M.

AU - Bedrosian, Isabelle

AU - Keyomarsi, Khandan

AU - Kuo, Wen Lin

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AU - Liu, Jinsong

AU - Halder, Georg

AU - Mills, Gordon

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N2 - We show that atypical PKCι, which plays a critical role in the establishment and maintenance of epithelial cell polarity, is genomically amplified and overexpressed in serous epithelial ovarian cancers. Furthermore, PKCι protein is markedly increased or mislocalized in all serous ovarian cancers. An increased PKCι DNA copy number is associated with decreased progression-free survival in serous epithelial ovarian cancers. In a Drosophila in vivo epithelial tissue model, overexpression of persistently active atypical PKC results in defects in apical-basal polarity, increased Cyclin E protein expression, and increased proliferation. Similar to the Drosophila model, increased PKCι proteins levels are associated with increased Cyclin E protein expression and proliferation in ovarian cancers. In nonserous ovarian cancers, increased PKCι protein levels, particularly in the presence of Cyclin E, are associated with markedly decreased overall survival. These results implicate PKCι as a potential oncogene in ovarian cancer regulating epithelial cell polarity and proliferation and suggest that PKCι is a novel target for therapy.

AB - We show that atypical PKCι, which plays a critical role in the establishment and maintenance of epithelial cell polarity, is genomically amplified and overexpressed in serous epithelial ovarian cancers. Furthermore, PKCι protein is markedly increased or mislocalized in all serous ovarian cancers. An increased PKCι DNA copy number is associated with decreased progression-free survival in serous epithelial ovarian cancers. In a Drosophila in vivo epithelial tissue model, overexpression of persistently active atypical PKC results in defects in apical-basal polarity, increased Cyclin E protein expression, and increased proliferation. Similar to the Drosophila model, increased PKCι proteins levels are associated with increased Cyclin E protein expression and proliferation in ovarian cancers. In nonserous ovarian cancers, increased PKCι protein levels, particularly in the presence of Cyclin E, are associated with markedly decreased overall survival. These results implicate PKCι as a potential oncogene in ovarian cancer regulating epithelial cell polarity and proliferation and suggest that PKCι is a novel target for therapy.

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