Cancer cell lines harboring PIK3CA mutations are really sensitive to PI3K pathway inhibitors, rendering this pathway a drug target of higher interest for cancer treatment. PIK3CA mutations have been located at related frequencies in breast ductal carcinoma in situ lesions, DCIS adjacent to invasive ductal carcinoma, and IDC, suggesting that these mutations are early events in breast tumorigenesis and as a result may possibly promote transformation of typical breast epithelial cells. A recent examine by Meyer and colleagues unveiled that expression in the PIK3CA H1047R mutant in mammary epithelial cells is sucient to induce tumor formation in transgenic mice. PIK3CA H1047R expres sion driven by Cre mediated recombination induced by both the WAP promoter or the MMTV promoter induced the formation of mammary tumors of varying histologic subtypes.
Tumor cells expressed markers related with both luminal and basal epithelial lineages, suggesting that tumors with basal traits can arise from luminal cells. The authors postulate that PIK3CA H1047R could transform multi potent progenitor cells to allow each luminal and basal dierentiation, induce de dieren tiation of luminal cells to multi potent progenitors, which then give rise to each lineages, selleck chemicals Wnt-C59 or do the two. Involuting mammary glands from PIK3CA H1047R mice showed a reduction within the quantity of apoptotic cells and delayed involution in comparison with controls. PIK3CA H1047R tumors also showed really minimal rates of apoptosis and increased ranges of phosphorylated AKT than mammary tumors from one more model, suggest ing that PIK3CA H1047R prevents cell death by elevated PI3K/AKT pathway activation. In a different review, Liu and colleagues reported that PIK3CA H1047R induced mammary tumors exhibit variable dependence on this oncogene.
Transgenic mice expressed selleckchem PIK3CA H1047R beneath the control of an MMTV regulated, doxycycline inducible system. Mice treated with doxycycline showed increased phospho AKT levels in mammary epithelial cells and formed mammary tumors of various histologic subtypes. Silencing of PIK3CA H1047R by withdrawal of doxycycline decreased tumor phospho AKT levels, decreased proliferation, increased apoptosis, and induced full tumor regression in one third of the mice. Two thirds of tumors partially regressed and after that resumed growth. Some recurrent tumors that maintained high levels of P AKT and P S6 had been sensitive on the PI3K inhibitor GDC 0941, whereas tumors with lower P AKT and P S6 were insensi tive to this agent. This suggests that some PIK3CA H1047R induced tumors escape from dependence on PI3K. GDC 0941 resistant and PIK3CA H1047R indepen dent tumors exhibited amplication of the oncogenes MYC, MDM2, and/or MET. The authors demonstrated tumor dependence on MYC and MET and showed that MYC overexpression circumvented depen dence on PI3K.