Targeting Akt in breast cancer: Studies using transgenic mice and inhibitory peptides
Akt is serine/threonine kinase which regulates multiple pathways in cells including apoptosis, cell division and homeostasis. These functions can be co-opted by cancer cells to allow for progression of the disease. To study the effects of Akt1 overexpression on the initiation of breast cancer, we generated transgenic mice which have targeted expression of human cAkt1 in mammary epithelial cells. While no evidence of tumor formation was found, mammary glands of transgenic mice were slow to involute following cessation of nursing, and some hyperplasia was present. Further analysis suggested a role for cyclin D1 in the inhibition of involution seen in transgenic mice.
The AH domain of Akt, comprising the first approximately 150 amino acids of the kinase, has been suggested to be a homodimerization domain. We used PCR to generate the AH domain of Akt1 and Akt2, and tested their ability to inhibit the Akt pathway. Both domains were effective at sensitizing U87 cells to camptothecin, and caused some basal apoptosis in several breast and prostate cancer cell lines. These peptides appear to be working via an Akt dependent mechanism, based on assays measuring AFX transcriptional activity. The mechanism of action of these peptides appears to be inhibition of activation loop phosphorylation by binding to Akt and either directly or indirectly blocking PDK1 activation of the kinase. These results suggest that the AH domain of Akt may be a favorable target for small molecule drug design.
0379: Cellular biology