|
| Status |
Public on Jun 20, 2013 |
| Title |
Conditional loss of ErbB3 delays mammary gland hyperplasias induced by mutant PIK3CA but does not affect mammary tumor latency, gene expression or signaling |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by array
|
| Summary |
Mutations in PIK3CA, the gene encoding the p110α subunit of PI3K, induce transformation of mammary epithelial cells (MEC). Studies suggest the transforming action of mutant PIK3CA requires binding to activated receptor tyrosine kinases or adaptors. We examined in transgenic mice if ErbB3, a powerful activator of PI3K, is required for mutant PIK3CA-mediated MEC transformation. ErbB3 loss delayed PIK3CAH1047R-dependent mammary gland hyperplasia, but tumor latency, gene expression and markers of PI3K signaling were unaffected. In ErbB3-deficient tumors, mutant PI3K remained associated with other tyrosine phosphorylated adaptors, potentially explaining the dispensability of ErbB3 for tumorigenicity and PI3K activity. Combined inhibition of ErbB RTKs and PI3K with lapatinib and the p110α inhibitor BYL719, respectively, reduced PIK3CAH1047R-dependent tumor growth and PI3K signaling more potently than the p110α inhibitor alone. In human breast cancer cells harboring PIK3CAH1047R, the combination with BYL719 and an ErbB3 inhibitor synergistically inhibited tumor growth and P-Akt. These data suggest that basal tumor growth and PI3K signaling do not depend on ErbB RTKs in PIK3CAH1047R-expressing tumors. However, upon inhibition of p110α, these receptors limit the action of PI3K inhibitors potentially explaining the more potent effect of the combination against PI3K-mutant cancers.
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| Overall design |
reference x sample
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| |
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| Contributor(s) |
Young CD, Pfefferle AD, Perou CM, Arteaga CL |
| Citation(s) |
23633485 |
| |
| Submission date |
Dec 19, 2012 |
| Last update date |
Jul 17, 2015 |
| Contact name |
Charles M. Perou |
| E-mail(s) |
cperou@med.unc.edu
|
| Organization name |
University of North Carolina at Chapel Hill
|
| Department |
Professor of Genetics, and Pathology & Laboratory Medicine; Lineberger Comprehensive Cancer Center
|
| Street address |
12-044 Lineberger Comprehensive Cancer Center CB# 7295
|
| City |
Chapel Hill |
| State/province |
NC |
| ZIP/Postal code |
27599-7264 |
| Country |
USA |
| |
|
| Platforms (1) |
| GPL11383 |
Agi-perou-lab-custom-MM-144K-arrays-BARCODE25503 |
|
| Samples (12)
|
| GSM1055294 |
Strain_FL/+_(HER3+/-_+PI3K)_10-287_Arteaga |
| GSM1055295 |
Strain_FL/+_(HER3+/-_+PI3K)_10-334_Arteaga |
| GSM1055296 |
Strain_FL/FL_(HER3-/-_+PI3K)_10-335_Arteaga |
| GSM1055297 |
Strain_FL/+_(HER3+/-_+PI3K)_10-336_Arteaga |
| GSM1055298 |
Strain_FL/FL_(HER3-/-_+PI3K)_10-337_Arteaga |
| GSM1055299 |
Strain_FL/FL_(HER3-/-_+PI3K)_11-067_Arteaga |
| GSM1055300 |
Strain_FL/+_(HER3+/-_+PI3K)_11-089_Arteaga |
| GSM1055301 |
Strain_FL/FL_(HER3-/-_+PI3K)_11-090_Arteaga |
| GSM1055302 |
Strain_FL/+_(HER3+/-_+PI3K)_11-107_Arteaga |
| GSM1055303 |
Strain_FL/FL_(HER3-/-_+PI3K)_11-108_Arteaga |
| GSM1055304 |
Strain_FL/+_(HER3+/-_+PI3K)_11-109_Arteaga |
| GSM1055305 |
Strain_FL/FL_(HER3-/-_+PI3K)_11-110_Arteaga |
|
| Relations |
| BioProject |
PRJNA184147 |
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