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

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