Abstract LB-42: In vivo screen for novel breast cancer promoting genes.

Abstract

Abstract Mis-regulation of oncogenes and tumor suppressor genes causes cancer. Although the evolution of cancer is not conclusive, most evidence supports that tumors arise from collaboration of multiple genes. To better understand the process of breast tumor initiation and cancer progression we carried out an in vivo screen, for genes that promote tumor formation. Our screen was performed using lentiviral transduction of primary murine mammary epithelial cells, and orthotopic implantation into syngeneic recipient mice. Wild type mammary stem cells can regenerate an entire mammary ductal tree in the recipients. We chose a well-characterized ErbB2/Her2 over-expression mouse model as a source of donor cells because HER2 over-expression occurs in >20% of human breast cancer patients. A cDNA library consisting of a “druggable” set of ~1000 genes was screened in 12 subsets segregated by ORF length. Ten months after transplantation the recipient mice were euthanized and DNA from mammary gland tumors was harvested. No tumors formed in mice transplanted with cells into which a control virus had been transduced. Genes from the library that were expressed in the tumors were identified by sequencing. The ability of these genes to drive tumor formation was confirmed by transduction and transplantation into a second cohort of mice. One of the genes identified in this screen is GTF2I repeat domain containing 1 (GTF2IRD1). Multi-focal atypical hyperplasia formed in mammary glands over-expressing GTF2IRD1 while no hyperplasia was seen in the control mice. This effect depends on the expression of ErbB2 because expression of GTF2IRD1 itself in wild type mammary glands did not cause abnormal growth before the end point. Analysis of the cancer genome atlas database demonstrates that GTF2IRD1 expression is significantly increased in invasive breast cancer compared to normal controls. Therefore, our screen has identified a novel tumor-promoting gene that is of potential clinical importance. A major advantage of our method is the use of normal cells of origin and immunocompetent mice. Moreover, it could be expanded to genome-wide searches for new tumor- and metastasis-promoting genes. Citation Format: Yongliang Huo, Ian Macara. In vivo screen for novel breast cancer promoting genes. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-42. doi:10.1158/1538-7445.AM2013-LB-42