Pleomorphic adenoma gene 1 (PLAG1) encodes a transcription factor that is involved in several human neoplasias such as in pleomorphic adenomas of the salivary glands, lipoblastoma, hepatoblastoma and AML. As an approach to assess the in vivo consequences of PLAG1 overexpression in the complex genetic background of a mammalian model system, two independent PLAG1 transgenic mouse strains, in which the activation of PLAG1 overexpression is Cre-mediated, were developed. Those founders were crossed with MMTV-Cre transgenic mice in order to target PLAG1 expression mainly to the salivary glands and the mammary glands. The resulting offspring, P1-Mcre and P2-Mcre mice, developed pleomorphic adenomas of the salivary glands with a prevalence of respectively, 100% at 5 weeks and 6% after several months. Moreover, 100% of the female P1-Mcre mice also showed metaplasia of the mammary glands at 8 weeks and 16% of the P2-Mcre females developed mammary gland adenomyoepitheliomas after a latency period of about a year. Igf2, one of the direct target genes of PLAG1, is highly upregulated in those tumors. To investigate whether or not Igf2 signaling is a key growth regulatory pathway in the tumor models, we knocked out the imprinted Igf2 gene in P1-Mcre mice. The tumor onset in P1-Mcre/Igf2m-/p- mice was clearly delayed by several weeks. This conclusively suggests that Igf2 indeed plays a role in tumorigenesis in these mouse models. However, other pathways are involved as well such as Wnt signaling. PLAG1 is also involved in lipoblastomas in human. Therefore we investigated the impact of AP2-Cre-mediated overexpression of PLAG1 in fat tissue. More than 80% of the double transgenic P1-Acre mice developed Cavernous angiomatosis within 1 year; however those mice did not develop lipoblastomas within this period. Finally we intercrossed the PLAG1 transgenic founder lines with Pdx1-Cre and RIP-Cre mice to investigate the impact of the targeted overexpression of PLAG1 in the whole pancreas and in the \#946;-cells respectively. The double transgenic offspring mice developed hyperplasia of the islets of Langerhans. In conclusion, we demonstrate that PLAG1 is involved in pleomorphic adenomas of the salivary glands, adenomyoepitheliomas of the mammary glands, cavernous angiomatosis and islet hyperplasia.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 4928.

100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO

American Association for Cancer Research
2009