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Conditional loss of ErbB3 delays mammary gland hyperplasia induced by mutant PIK3CA without affecting mammary tumor latency, gene expression, or signaling.

Young CD, Pfefferle AD, Owens P, Kuba MG, Rexer BN, Balko JM, Sánchez V, Cheng H, Perou CM, Zhao JJ, Cook RS, Arteaga CL
Cancer Res. 2013 73 (13): 4075-85

PMID: 23633485 · PMCID: PMC3702683 · DOI:10.1158/0008-5472.CAN-12-4579

Mutations in PIK3CA, the gene encoding the p110α catalytic subunit of phosphoinositide 3-kinase (PI3K), have been shown to transform mammary epithelial cells (MEC). Studies suggest this transforming activity requires binding of mutant p110α via p85 to phosphorylated YXXM motifs in activated receptor tyrosine kinases (RTK) or adaptors. Using transgenic mice, we examined if ErbB3, a potent activator of PI3K, is required for mutant PIK3CA-mediated transformation of MECs. Conditional loss of ErbB3 in mammary epithelium resulted in a delay of PIK3CA(H1047R)-dependent mammary gland hyperplasia, but tumor latency, gene expression, and PI3K signaling were unaffected. In ErbB3-deficient tumors, mutant PI3K remained associated with several tyrosyl phosphoproteins, potentially explaining the dispensability of ErbB3 for tumorigenicity and PI3K activity. Similarly, inhibition of ErbB RTKs with lapatinib did not affect PI3K signaling in PIK3CA(H1047R)-expressing tumors. However, the p110α-specific inhibitor BYL719 in combination with lapatinib impaired mammary tumor growth and PI3K signaling more potently than BYL719 alone. Furthermore, coinhibition of p110α and ErbB3 potently suppressed proliferation and PI3K signaling in human breast cancer cells harboring PIK3CA(H1047R). These data suggest that PIK3CA(H1047R)-driven tumor growth and PI3K signaling can occur independently of ErbB RTKs. However, simultaneous blockade of p110α and ErbB RTKs results in superior inhibition of PI3K and mammary tumor growth, suggesting a rational therapeutic combination against breast cancers harboring PIK3CA activating mutations.

©2013 AACR.

MeSH Terms (25)

Animals Antineoplastic Agents Cell Line, Tumor Class I Phosphatidylinositol 3-Kinases Female Gene Expression Humans Hyperplasia Lapatinib Mammary Glands, Animal Mammary Neoplasms, Experimental Mice Mice, Nude Mice, Transgenic Mutation, Missense Neoplasm Transplantation Phosphatidylinositol 3-Kinases Phosphoinositide-3 Kinase Inhibitors Protein Binding Quinazolines Receptor, ErbB-2 Receptor, ErbB-3 Signal Transduction Transcriptome Tumor Burden

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