ERAS, a Member of the Ras Superfamily, Acts as an Oncoprotein in the Mammary Gland

SIMPLE SUMMARY: The genes of the RAS family are among the group of genes most frequently mutated in human cancer. ERAS is a relatively unknown gene of this family. Although ERAS is overexpressed in some tumoral samples and in several cancer cell lines of human origin, it is not known if its expression drives tumor formation or if, alternatively, its expression is a secondary event in tumoral transformation. In this report, in order to clarify the role of ERAS in mammary tumorigenesis, we studied transgenic mice expressing ERAS in myoepithelial cells of mammary and other exocrine glands and in basal cells of stratified epithelia. These mice displayed an altered development and function of the mammary glands, and suffered high-frequency tumoral lesions in the mammary glands resembling a rare human breast tumor named malignant adenomyoepithelioma. Our results clearly demonstrate that ERAS is a true oncogene able to produce mammary tumors when inappropriately expressed. ABSTRACT: ERAS is a relatively uncharacterized gene of the Ras superfamily. It is expressed in ES cells and in the first stages of embryonic development; later on, it is silenced in the majority of cell types and tissues. Although there are several reports showing ERAS expression in tumoral cell lines and human tumor samples, it is unknown if ERAS deregulated expression is enough to drive tumor development. In this report, we have generated transgenic mice expressing ERAS in myoepithelial basal cells of the mammary gland and in basal cells of stratified epithelia. In spite of the low level of ERAS expression, these transgenic mice showed phenotypic alterations resembling overgrowth syndromes caused by the activation of the AKT-PI3K pathway. In addition, their mammary glands present developmental and functional disabilities accompanied by morphological and biochemical alterations in the myoepithelial cells. These mice suffer from tumoral transformation in the mammary glands with high incidence. These mammary tumors resemble, both histologically and by the expression of differentiation markers, malignant adenomyoepitheliomas. In sum, our results highlight the importance of ERAS silencing in adult tissues and define a truly oncogenic role for ERAS in mammary gland cells when inappropriately expressed.