Abstract 4457: Determining the role of novel GLI1 splice variants in breast cancer

Abstract

Abstract The purpose of this study is to investigate the biological significance of novel GLI1 splice variants in breast cancer. 15-20% of breast cancers are triple negative/basal-like, are associated with poor clinical outcomes and show disproportionately higher prevalence in younger women of African descent. The Hedgehog (Hh)/GLI1 developmental pathway has emerged as a therapeutic target in many cancers including studies on breast cancer such as those from our lab. Overexpression of the main Hh transcriptional mediator GLI1 correlates with poor patient prognosis and relapse. The human GLI1 transcript undergoes alternative splicing producing two shorter isoforms, an N-terminal deletion variant (GLI1ΔN) and a truncated GLI1 (tGLI1) which have been reported to have different patterns of tissue expression and function. tGLI1 has been identified as being highly expressed in several cancers, including in breast cancer. We undertook an in silico analysis of the NCBI database for evidence of additional human GLI1 transcripts and have identified novel GLI1 splice variants that we have subsequently shown to be highly expressed in breast cancer cell lines. Our objectives were to examine expression differences between GLI1 splice variants in basal-like and luminal breast cancer cell models, AA and White patient samples and to investigate the biological function of GLI1 splice variants in breast cancer. In our studies, we have utilized phenotypic and functional assays to examine the functional impact of these novel isoforms. Our preliminary data suggest that these newly identified GLI1 isoforms are expressed in basal-like breast cancers at substantially higher levels than GLI1, tGLI1 or GLI1ΔN. Previous studies assessing GLI1 expression have not considered these new isoforms and the relative contribution of each to breast cancer aggressiveness and require further investigation. Citation Format: Maria S. Dixon, Lhoucine Chdid, David Lamson, Michael Tarpley, Jodie M. Fleming, Jennifer A. Freedman, Gayathri R. Devi, Kevin P. Williams. Determining the role of novel GLI1 splice variants in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4457.