Abstract 3404: Identifying genes involved in retinoic-acid-mediated breast tumor progression by total-genome-knockdown screen

Abstract

Abstract Despite numerous advances in cancer care, breast cancer remains one of the leading causes of cancer-related death among Canadian women. Previous work by our lab has identified aldehyde dehydrogenase 1A3 (ALDH1A3) as a breast cancer stem cell marker, and patients with high levels of ALDH1A3 in their tumors have worse outcomes. Furthermore, we found that via its retinoic acid (RA) production function, ALDH1A3 also contributes to breast tumor growth and metastasis in a murine xenograft model. RA induces transcription of many genes (directly and indirectly), initiates cell signaling and regulates many cellular processes involved in cell growth and differentiation. To identify the key RA-inducible genes which mediate breast cancer progression we performed a genome-wide lentiviral-based shRNA screen using MDA-MB-231 breast cancer cells xenotransplanted into NOD/SCID mice with or without RA treatment. From the in vivo screen, 50 genes were identified as being putatively involved in RA-mediated breast tumor growth. 14 genes have been confirmed in vitro as differentially expressed in the presence of RA. We have generated individual shRNA knockdown clones of the genes and are validating their involvement in RA-mediated breast cancer progression in vivo. Analysis of the genes identified by this screen revealed potential interactions between RA and Wnt signaling, implicating extensive cross-talk between these two pathways. Completion of this study will define the mechanism of RA-mediated breast cancer progression and potentially identify new therapeutic targets for breast cancer treatment. Citation Format: Krysta M. Coyle, Cheryl Dean, Lu-Zhe Pan, Dae-Gyun Ahn, Mohammad Sultan, Jayme Salsman, Graham Dellaire, Carman Giacomantonio, Patrick W. Lee, Paola Marcato. Identifying genes involved in retinoic-acid-mediated breast tumor progression by total-genome-knockdown screen. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3404. doi:10.1158/1538-7445.AM2014-3404