Akt1 and akt2 play distinct roles in the initiation and metastatic phases of mammary tumor progression.

The phosphatidylinositol 3-kinase (PI3K)/Akt survival pathway is often dysregulated in cancer. Our previous studies have shown that coexpression of activated Akt1 with activated ErbB2 or polyoma virus middle T antigen uncoupled from the PI3K pathway (PyVmT Y315/322F) accelerates mammary tumor development but cannot rescue the metastatic phenotype associated with these models. Here, we report the generation of transgenic mice expressing activated Akt2 in the mammary epithelium. Like the mouse mammary tumor virus-Akt1 strain, mammary-specific expression of Akt2 delayed mammary gland involution. However, in contrast to Akt1, coexpression of Akt2 with activated ErbB2 or PyVmT Y315/322F in the mammary glands of transgenic mice did not affect the latency of tumor development. Strikingly, Akt2 coexpresssion markedly increased the incidence of pulmonary metastases in both tumor models, demonstrating a unique role in tumor progression. Together, these observations argue that these highly conserved kinases have distinct biological and biochemical outputs that play opposing roles in mammary tumor induction and metastasis.

[1]  S. Naber,et al.  Distinct roles of the three Akt isoforms in lactogenic differentiation and involution , 2008, Journal of cellular physiology.

[2]  Zhi Hu,et al.  An integrative genomic and proteomic analysis of PIK3CA, PTEN, and AKT mutations in breast cancer. , 2008, Cancer research.

[3]  Yiling Lu,et al.  Pharmacodynamic Markers of Perifosine Efficacy , 2007, Clinical Cancer Research.

[4]  Xuming He,et al.  Non-parametric quantification of protein lysate arrays , 2007, Bioinform..

[5]  Robert D. Cardiff,et al.  Insights from transgenic mouse models of ERBB2-induced breast cancer , 2007, Nature Reviews Cancer.

[6]  Jie Zhou,et al.  Akt1 governs breast cancer progression in vivo , 2007, Proceedings of the National Academy of Sciences.

[7]  W. Muller,et al.  The phosphatidyl inositol 3-kinase signaling network: implications for human breast cancer , 2007, Oncogene.

[8]  G. Mills,et al.  Reverse phase protein array: validation of a novel proteomic technology and utility for analysis of primary leukemia specimens and hematopoietic stem cells , 2006, Molecular Cancer Therapeutics.

[9]  E. Tokunaga,et al.  The association between Akt activation and resistance to hormone therapy in metastatic breast cancer. , 2006, European journal of cancer.

[10]  J. Brugge,et al.  Distinct roles of Akt1 and Akt2 in regulating cell migration and epithelial–mesenchymal transition , 2005, The Journal of cell biology.

[11]  A. Toker,et al.  Akt blocks breast cancer cell motility and invasion through the transcription factor NFAT. , 2005, Molecular cell.

[12]  S. Johnston.  Combinations of endocrine and biological agents: present status of therapeutic and presurgical investigations. , 2005, Clinical cancer research : an official journal of the American Association for Cancer Research.

[13]  Robert D Cardiff,et al.  Activation of Akt-1 (PKB-alpha) can accelerate ErbB-2-mediated mammary tumorigenesis but suppresses tumor invasion. , 2004, Cancer research.

[14]  Jiang Shou,et al.  Cross-Talk between Estrogen Receptor and Growth Factor Pathways as a Molecular Target for Overcoming Endocrine Resistance , 2004, Clinical Cancer Research.

[15]  R. Cardiff,et al.  Gene expression profiling of neu-induced mammary tumors from transgenic mice reveals genetic and morphological similarities to ErbB2-expressing human breast cancers. , 2003, Cancer research.

[16]  J. McManaman,et al.  during pregnancy , 2003 .

[17]  R. Glazer,et al.  Delayed mammary gland involution in MMTV-AKT1 transgenic mice , 2002, Oncogene.

[18]  H. Kurokawa,et al.  Inhibition of erbB receptor (HER) tyrosine kinases as a strategy to abrogate antiestrogen resistance in human breast cancer. , 2001, Clinical cancer research : an official journal of the American Association for Cancer Research.

[19]  S. Anderson,et al.  Mammary gland involution is delayed by activated Akt in transgenic mice. , 2001, Molecular endocrinology.

[20]  R. Cardiff,et al.  Activation of Akt (Protein Kinase B) in Mammary Epithelium Provides a Critical Cell Survival Signal Required for Tumor Progression , 2001, Molecular and Cellular Biology.

[21]  M. Rudnicki,et al.  Amplification of the neu/erbB-2 oncogene in a mouse model of mammary tumorigenesis. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[22]  R. Cardiff,et al.  Elevated expression of activated forms of Neu/ErbB‐2 and ErbB‐3 are involved in the induction of mammary tumors in transgenic mice: implications for human breast cancer , 1999, The EMBO journal.

[23]  P. Vogt,et al.  The akt kinase: molecular determinants of oncogenicity. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[24]  John N. Hutchinson,et al.  Requirement for Both Shc and Phosphatidylinositol 3′ Kinase Signaling Pathways in Polyomavirus Middle T-Mediated Mammary Tumorigenesis , 1998, Molecular and Cellular Biology.

[25]  H. Rochefort,et al.  Breast cancer cell invasiveness: Correlation with protein kinase C activity and differential regulation by phorbol ester in estrogen receptor‐positive and ‐negative cells , 1998, International journal of cancer.

[26]  Robert Clarke,et al.  Association of increased basement membrane invasiveness with absence of estrogen receptor and expression of vimentin in human breast cancer cell lines , 1992, Journal of cellular physiology.

[27]  J. Price,et al.  Tumorigenicity and metastasis of human breast carcinoma cell lines in nude mice. , 1990, Cancer research.

[28]  B E Griffin,et al.  Monoclonal antibodies against polyoma virus tumor antigens. , 1982, Proceedings of the National Academy of Sciences of the United States of America.

[29]  W. E. Gye,et al.  CANCER RESEARCH , 1923, British medical journal.

[30]  S. Naber,et al.  Akt1 ablation inhibits, whereas Akt2 ablation accelerates, the development of mammary adenocarcinomas in mouse mammary tumor virus (MMTV)-ErbB2/neu and MMTV-polyoma middle T transgenic mice. , 2007, Cancer research.

[31]  H. Kurokawa,et al.  ErbB (HER) receptors can abrogate antiestrogen action in human breast cancer by multiple signaling mechanisms. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[32]  M. Dowsett,et al.  Integration of signal transduction inhibitors with endocrine therapy: an approach to overcoming hormone resistance in breast cancer. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.