Abstract C100: Identification and functional characterization of a novel GLI1 splice variant in breast cancer

Abstract

Abstract The purpose of this study is to investigate the biologic significance of novel GLI1 splice variants in breast cancer. African American (AA) women suffer a disproportionately high burden of basal-like breast cancer, an aggressive subtype that has no targeted therapy (1). About 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 (2-4). The Hedgehog (Hh)/GLI1 developmental pathway has emerged as a therapeutic target in many cancers, including breast cancer studies from our lab (5, 6). 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) (7) and a truncated GLI1 (tGLI1) (8), 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 (9). We performed in silico analysis of the NCBI database for evidence of additional human GLI1 transcripts and identified a novel GLI1 splice variant, GLI1-X2, that has an in-frame deletion of the entire exon 10-zinc finger 5 domain of the GLI1 gene. Our preliminary data show that GLI1-X2 is expressed in basal-like breast cancers at substantially higher levels than GLI1, tGLI1, or GLI1ΔN. To our knowledge, we are the first to demonstrate expression of GLI1-X2 in any model and our findings expand the GLI1 family of zinc finger transcription factors. Our objectives are to examine the expression differences of the GLI1 splice variants in basal-like and luminal breast cancer cell models, AA and White patient samples and to investigate the biologic function of GLI1-X2 in breast cancer. Previous studies report that GLI1ΔN and tGLI1 proteins retain intact functional zinc finger domains. Thus, we hypothesize that the loss of zinc-finger 5 is critical for GLI1-X2's functional role and regulation of downstream target genes in breast cancer. As the biologic significance of GLI1-X2 in normal and cancer biology is unknown, this proposed work is the first to characterize its function and potential role in cancer. Citation Format: Maria S. Dixon, Lhoucine Chdid, David R. Lamson, Michael T. Tarpley, Helen O. Oladapo, Jodie M. Fleming, Jennifer A. Freedman, Gayathri R. Devi, Kevin P. Williams. Identification and functional characterization of a novel GLI1 splice variant in breast cancer [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr C100.