Mechanisms of polyomavirus transformation of the mouse mammary gland

Abstract

<p>Polyomavirus infection of newborn rodents results in the rapid induction of tumor formation in a number of tissues. One of the prominent target organs for Polyomavirus-mediated transformation is the mammary gland. The transforming potential of Polyomavirus (PyV) resides in the cellular expression of three tumor antigens (large, middle, and small) immediately following viral absorption. Due to the potent transforming ability of these T antigens in the mouse mammary gland, and given the extensive characterization of cellular proteins which interact with the various T antigens, I sought to exploit the use of these viral oncogenes to elucidate cellular proteins critical in this transformation process. To analyze the functional significance of large T antigen expression in the mouse mammary gland, I generated transgenic mice harboring the PyV LT antigen cDNA under transcriptional control of the mouse mammary tumor virus long terminal repeat (MMTV LTR). While PyV LT expression was correlated with the genesis of mammary dysplasia, the latency, frequency, and focal nature with which tumors arise suggests that PyV LT is not sufficient to induce malignant conversion of the primary mammary epithelial cell. PyV MT efficiently transforms the mouse mammary epithelium. To better elucidate which signal transduction pathways central to this process, I have generated mouse models which effectively demonstrate the in vivo role(s) of three MT-associated proteins in mammary tumorigenesis - Src, SHC, and phosphatidylinositol 3-kinase. To directly assess the effect of mammary gland-specific expression of activated c-Src, I established transgenic mice which carry a constitutively activated form of c-src under the transcriptional control of the MMTV LTR. The roles of both SHC and Pl3'K were investigated through functional inactivation of the corresponding binding sites for these proteins of PyV MT. These mutant MT isoforms were used to generate MMTV/MT Y250F and MMTV/MT Y315/22F strains respectively. Similar to PyV LT transgenic strains, Src527F, MT Y250F, and MT Y315/22F strains all were debilitated in mammary tumor formation compared to wild-type PyV MT transgenic animals.</p>