Atypical PKCiota contributes to poor prognosis through loss of apical-basal polarity and cyclin E overexpression in ovarian cancer.
We show that atypical PKCiota, 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, PKCiota protein is markedly increased or mislocalized in all serous ovarian cancers. An increased PKCiota 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 PKCiota proteins levels are associated with increased Cyclin E protein expression and proliferation in ovarian cancers. In nonserous ovarian cancers, increased PKCiota protein levels, particularly in the presence of Cyclin E, are associated with markedly decreased overall survival. These results implicate PKCiota as a potential oncogene in ovarian cancer regulating epithelial cell polarity and proliferation and suggest that PKCiota is a novel target for therapy.
Eder
Astrid M
AM
Department of Molecular Therapeutics, M. D. Anderson Cancer Center, University of Texas, Houston, TX 77030, USA.
Sui
Xiaomei
X
Rosen
Daniel G
DG
Nolden
Laura K
LK
Cheng
Kwai Wa
KW
Lahad
John P
JP
Kango-Singh
Madhuri
M
Lu
Karen H
KH
Warneke
Carla L
CL
Atkinson
Edward N
EN
Bedrosian
Isabelle
I
Keyomarsi
Khandan
K
Kuo
Wen-lin
WL
Gray
Joe W
JW
Yin
Jerry C P
JC
Liu
Jinsong
J
Halder
Georg
G
Mills
Gordon B
GB
D000818:Animals; D030801:Animals, Genetically Modified; D017209:Apoptosis; D016764:Cell Polarity; D049109:Cell Proliferation; D019927:Cyclin E / Q000378:metabolism*; D004330:Drosophila / Q000166:cytology / Q000201:enzymology / Q000235:genetics; D005123:Eye / Q000166:cytology / Q000201:enzymology / Q000254:growth & development; D005260:Female; D005784:Gene Amplification; D006801:Humans; D007527:Isoenzymes / Q000235:genetics* / Q000378:metabolism*; D009857:Oncogenes; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D011379:Prognosis; D011493:Protein Kinase C / Q000235:genetics* / Q000378:metabolism*; D051381:Rats; D000099293:Protein Kinase C-lambda
D019927:Cyclin E; D007527:Isoenzymes; D011493:Protein Kinase C; D000099293:Protein Kinase C-lambda