Abstract
One of the most frequently deregulated signaling pathways in breast cancer is the PI 3-K/Akt cascade. Genetic lesions are commonly found in PIK3CA, PTEN, and AKT, which lead to excessive and constitutive activation of Akt and downstream signaling that results in uncontrolled proliferation and increased cellular survival. One such genetic lesion is the somatic AKT1(E17K) mutation, which has been identified in 4-8% of breast cancer patients. To determine how this mutation contributes to mammary tumorigenesis, we constructed a genetically engineered mouse model that conditionally expresses human AKT1(E17K) in the mammary epithelium. Although AKT1(E17K) 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(E17K) mice develop mammary gland hyperplasia that do not progress to carcinoma. This hyperplasia is accompanied by increased estrogen receptor expression, although exposure of the mice to estrogen does not promote tumor development. Moreover, AKT1(E17K) 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(E17K).
Highlights
One of the most frequently deregulated pathways in human cancers is the phosphoinositide 3-kinase (PI 3-K) and Akt signaling cascade [1]
Since the AKT1(E17K) somatic mutation is only detected in patients with ERpositive breast tumors [16], we evaluated whether exposure to estradiol accelerates the mammary tumor virus (MMTV)-tTA;hAKT1(E17K) mammary gland phenotype
AKT1(E17K) can drive transformation of fibroblasts in vitro [7] and enhances the survival and migration of luminal breast epithelial cells [18], we find that expression of AKT1(E17K) in MCF10A cells does not strongly activate downstream signaling, nor does it enhance proliferation, consistent with previous findings [17]
Summary
One of the most frequently deregulated pathways in human cancers is the phosphoinositide 3-kinase (PI 3-K) and Akt signaling cascade [1] This is evident in breast cancer where mutations exist in virtually all of the proteins that lead to activation of PI 3-K and its downstream effectors. PIP3 functions as a true second messenger by recruiting multiple effector molecules, one of which is the Akt/ PKB protein kinase that directly binds to PIP3 through its pleckstrin homology (PH) domain. This binding facilitates the phosphorylation of Akt at Thr308 and Ser473 mediated by phosphoinositide-dependent kinase-1 (PDK-1) and mammalian target of rapamycin complex 2 (mTORC2), respectively [2]. The Akt family comprises three isoforms - AKT1 (PKBα), AKT2 (PKBβ), and AKT3 (PKBγ) - which have nonredundant functions in various physiological as well as pathophysiological conditions [4]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
