The anti-apoptotic serine threonine kinase AKT1 is often activated in human cancers, and might contribute to tumour progression and metastasis. However, previous studies, primarily in cell lines, have shown conflicting results. Therefore, Richard Pestell and colleagues used Akt1-null mice to examine the role of AKT1 in a mouse model of breast cancer.
Akt1-/- mice were crossed with mice that overexpressed the receptor tyrosine kinase Erbb2 (also known as Her2) in the mammary epithelium. Erbb2;Akt1-/- mice rarely developed tumours, but Erbb2;Akt1+/+ mice developed tumours with a mean onset of about 210 days. Examination of six cell lines derived from tumours in Erbb2;Akt1-/- and Erbb2;Akt1+/+ mice indicated that the loss of AKT1 reduced the rate of proliferation and the physical size of the cells. A characteristic of ERBB2-expressing mammary epithelial cells grown in three-dimensional Matrigel cultures is a loss of cell polarity. In Matrigel cultures, cells derived from Erbb2;Akt1+/+ tumours had disrupted apicobasal polarity, but those that lacked AKT1 retained polarity. This indicates that AKT1 activity contributes to cellular disorganization and a loss of polarity induced by oncogenes, in addition to inducing the survival, growth and proliferation of tumour cells.
Tumour progression in the Erbb2;Akt1+/+ mice was characterized by the development of lung metastases, but this was not the case in the few tumours that did develop in Erbb2;Akt1-/- mice, even though they were of a similar size to Erbb2;Akt1+/+ tumours. How does AKT1 affect tumour metastasis? The authors found that the loss of AKT1 reduced cell migration. Migration seemed to be controlled by factors secreted by Erbb2;Akt1+/+ cells, as culture media taken from these cells rescued the migratory defect of Akt1-null cells. Using a cytokine antibody array, the authors found a more than 90% decrease in the levels of the chemokines CXCL16 and MIP1
(also known as CCL9) secreted by Erbb2;Akt1-/- cells compared with Erbb2;Akt1+/+ cells. Neutralizing antibodies to these chemokines reduced the migration of Erbb2;Akt1+/+ cells, and the addition of CXCL16 or MIP1 to Erbb2;Akt1-/- cells increased migration.
Pestell and colleagues have shown that AKT1 has several roles in mammary tumour progression in mice that express the oncogene Erbb2, and their results indicate that targeting AKT1 might have an effect on breast cancer at various stages of development.