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Oncotarget published "Oncogenic AKT1(E17K) mutation induces mammary hyperplasia but prevents HER2-driven tumorigenesis" which reported that one such genetic lesion is the somatic AKT1 mutation, which has been identified in 4-8% of breast cancer patients. To determine how this mutation contributes to mammary tumorigenesis, the authors constructed a genetically engineered mouse model that conditionally expresses human AKT1 in the mammary epithelium. Although AKT1 is only weakly constitutively active and does not promote proliferation in vitro, it is capable of escaping negative feedback inhibition to exhibit sustained signaling dynamics in vitro. Consistently, both virgin and multiparous AKT1 mice develop mammary gland hyperplasia that do not progress to carcinoma. Moreover, AKT1 prevents HER2-driven mammary tumor formation, in part through negative feedback inhibition of RTK signaling. Analysis of TCGA breast cancer data revealed that the mRNA expression, total protein levels, and phosphorylation of various RTKs are decreased in human tumors harboring AKT1. Dr. Alex Toker from Harvard Medical School said, "One of the most frequently deregulated pathways in human cancers is the phosphoinositide 3-kinase (PI 3-K) and Akt signaling cascade." Other breast cancer mutations prevalent in this pathway include mutational or epigenetic inactivation of Phosphatase and Tensin Homolog, a lipid phosphatase that terminates PI 3-K signaling by dephosphorylating PIP3. Both oncogenic PIK3CA mutations and inactivation of PTEN lead to excessive and constitutive activation of Akt and downstream signaling, resulting in uncontrolled proliferation and increased cellular survival . In the context of breast cancer, the AKT1 somatic mutation was first identified in breast cancer but is also found in lung, bladder, endometrial, urothelial and prostate cancers.