Carcinogenesis Advance Access originally published online on October 17, 2006
Carcinogenesis 2007 28(3):584-594; doi:10.1093/carcin/bgl190
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Mice expressing myrAKT1 in the mammary gland develop carcinogen-induced ER-positive mammary tumors that mimic human breast cancer
1 Experimental Therapeutics Programme, Spanish National Cancer Center (CNIO) Madrid, Spain
2 Biotechnology Programme, Spanish National Cancer Center (CNIO) Madrid, Spain
3 Present address: Anatomy pathology service, Hospital General de Palencia ‘Río Carrión’ Palencia, Spain
*To whom correspondence should be addressed at: Experimental Therapeutics Programme, Spanish National Cancer Center (CNIO), c/o Melchor Fernández Almagro n 3; 28029 Madrid, Spain. Tel: +34 91 732 8021; Fax: +34 91 224 6976; Email: acarnero{at}cnio.es
AKT1/PKB is a serine/threonine protein kinase that regulates biological processes such as proliferation, apoptosis and growth in a variety of cell types. To assess the oncogenic capability of an activated form of AKT in vivo we have generated several transgenic mouse lines that overexpress in the mammary epithelium the murine Akt1 gene modified with a myristoylation signal, which renders active this protein by localizing it to the plasma membrane. We demonstrate that expression of myristoylated AKT in the mammary glands increases the susceptibility of these mice to the induction of mammary tumors of epithelial origin by the carcinogen 9,10-dimethyl-1,2 benzanthracene (DMBA). We have found that while carcinogen-treated wild-type mice show mostly mammary tumors of sarcomatous origin, AKT transgenic mice treated with DMBA developed mainly adenocarcinoma or adenosquamous tumors, all of them displaying activated AKT. We analyzed other possible molecular alterations cooperating with AKT and found that neither Ras nor ß-catenin/Wnt pathways seemed altered nor p53 mutated. We have found that 100% of mammary DMBA-induced tumors and benign lesions in myrAKT mice are estrogen receptor (ER
)-positive and are more frequent than in wild-type littermates. These data show that AKT activation cooperates with deregulation of the estrogen receptor in the DMBA-induced mammary tumorigenesis model and recapitulate two characteristics of some human breast tumors. Thus, our model might provide a preclinical relevant model system to study the role of AKT and ER in breast tumorigenesis and the response of mammary gland tumors to chemotherapeutics.
Abbreviations: DMBA, 9,10-dimethyl-1,2-benzanthracene; MIN, mammary intraepithelial neoplasia; MMTV, mouse mammary tumor virus; PDK1, 3-phosphoinositide-dependent protein kinase-1; TMA, tissue microarray
Received July 4, 2006; revised September 25, 2006; accepted October 2, 2006.
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