Abstract 659: Novel refinements for the autochthonous mouse model of cancer

Abstract

Abstract There are many levels of genetic regulation at play in autochthonous mouse models of cancer. For instance, mouse models can be programed to knockout tumor suppressor genes and enable transcription of oncogenes in order to cause normal cells to transform into cancer cells that can eventually form tumors and metastasize. Concurrently to this, a gene of interest (GOI) under the control of a tetracycline-response element (TRE) promoter can be studied in a doxycycline-dependent fashion. The GOI under the control of the TRE promoter will be transcribed only in the presence of a transcriptional activator fusion protein, rtTA, and a chemical compound, doxycycline. Unfortunately, it is extremely difficult to limit the doxycycline-dependent expression of the GOI only to cancer cells, so normal cells will invariably express the GOI. This inaccuracy can limit the translation of results from mouse model to human patient. In the interest of engineering models that closely recapitulate the disease in question, we propose to limit the expression of rtTA and the GOI to cancer cells by linking rtTA expression to cell cycle regulation. The cell cycle is leveraged because rapid division and proliferation are characteristics intrinsic to proliferative cancer cells, and some cell cycle proteins are abundantly expressed in cancer cells but not expressed in normal cells. By fusing rtTA to cell cycle proteins that are expressed in cycling cancer cells, we hope to improve the accuracy and capabilities of the autochthonous mouse model of cancer. Citation Format: Peter K. Cabeceiras, Nikhil S. Joshi, Tyler Jacks. Novel refinements for the autochthonous mouse model of cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 659.