Signaling through the PI 3-K, Akt and SGK Pathway in Breast Cancer Progression

The aggressive behavior of malignant breast cancer is determined by a complex array of signaling pathways that regulate cell growth, survival and migration. The PI 3-K-Akt pathway has been linked to all of these responses. The current paradigm states that deregulated PI 3-K-Akt signaling promotes cancer progression. Many of the enzymes that regulate PI 3-K signaling are frequently mutated in human breast cancer, thereby up-regulating Akt activity and increasing tumor cell growth and survival. This is best illustrated by the finding that the catalytic subunit of PI 3-K, PIK3CA, is the most frequently mutated oncogene in breast cancer. However, recent studies have demonstrated that distinct Akt isoforms can either inhibit or enhance breast cancer cell invasive migration and metastasis in vitro and in vivo, probably by phosphorylating a different set of substrates in an isoform specific manner. Afadin is a Ras target gene that regulates cell-cell adhesion downstream of Ras. Afadin protein loss of expression is associated with poor outcome in breast cancer patients. The most significant finding of this research thus far is that Afadin isoform 3, which is the longer, ubiquitously expressed form of the protein, is a substrate of Akt, down stream of the PI-3K pathway.
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