Activation of Akt-1 (PKB-α) Can Accelerate ErbB-2-Mediated Mammary Tumorigenesis but Suppresses Tumor Invasion

Abstract

Elevated expression of Akt-1 (PKBα) has been noted in a significant percentage of primary human breast cancers. Another frequent event in the genesis of human breast cancers is amplification and overexpression of the ErbB-2 receptor tyrosine kinase, an event which is associated with activation of Akt-1. To directly assess the importance of Akt-1 activation in ErbB-2 mammary tumor progression, we interhred separate strains of transgenic mice carrying mouse mammary tumor virus/activated Akt-1 and mouse mammary tumor virus/activated ErbB-2 to derive progeny that coexpress the transgenes in the mammary epithelium. Female transgenic mice coexpressing activated Akt-1 and ErbB-2 develop multifocal mammary tumors with a significantly shorter latency period than mice expressing activated ErbB-2 alone. This dramatic acceleration of mammary tumor progression correlates with enhanced cellular proliferation, elevated Cyclin D1 protein levels, and phosphorylation of retinoblastoma protein. These bitransgenic mammary tumors also exhibit lower levels of invasion into the surrounding tissue and more differentiated phenotypes. Consistent with these observations, female mice coexpressing activated Akt-1 and ErbB-2 developed significantly fewer metastatic lesions than the activated ErbB-2 strain alone. Taken together, these observations suggest that activation of Akt-1 during ErbB-2-induced mammary tumorigenesis may have opposing effects on tumor growth and metastatic progression.