Abstract
PIK3CA mutations confer constitutive activation of PI3K, which initiates intracellular kinase signaling cascades that promote cell proliferation and survival. Recent studies by Meyer and colleagues, and Liu and colleagues demonstrate that expression of the H1047R exon 20 mutant of PIK3CA in luminal mammary epithelial cells induces tumorigenesis, implying that PIK3CA mutation is an early event in breast cancer. PIK3CA-H1047R-initiated tumors exhibit variable dependence on the oncogene and variable sensitivity to PI3K inhibition. Amplification of the oncogenes MYC and MET was observed in tumors that recurred following silencing of PIK3CA-H1047R, suggesting that these pathways represent mechanisms of escape from PI3K inhibition.
Highlights
PIK3CA mutations confer constitutive activation of Phosphatidylinositol 3-kinase (PI3K), which initiates intracellular kinase signaling cascades that promote cell proliferation and survival
PIK3CA-H1047R expression driven by Cre-mediated recombination induced by either the WAP promoter or the MMTV promoter induced the formation of mammary tumors of varying histologic subtypes
Mice treated with doxycycline showed increased phospho-AKT levels in mammary epithelial cells and formed mammary tumors of varying histologic subtypes
Summary
PIK3CA mutations confer constitutive activation of PI3K, which initiates intracellular kinase signaling cascades that promote cell proliferation and survival. A recent study by Meyer and colleagues [9] revealed that expression of the PIK3CA-H1047R mutant in mammary epithelial cells is sufficient to induce tumor formation in transgenic mice. PIK3CAH1047R tumors showed very low rates of apoptosis and higher levels of phosphorylated AKT than mammary tumors from another model (MMTV-NeuNT), suggesting that PIK3CA-H1047R prevents cell death by increased PI3K/AKT pathway activation.
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