Abstract B47: Efficacy of GLI antagonists in triple-negative inflammatory breast cancer 2D and 3D models

Abstract

Abstract Our objective was to investigate the differential effects of specific GLI1 antagonists in triple-negative inflammatory breast cancer 2D and 3D cell culture systems. Inflammatory breast cancer (IBC) accounts for 15% of all breast cancer deaths. IBC is a unique form of locally advanced breast cancer, an aggressive and highly invasive breast cancer having one of the worst clinical outcomes among breast cancers. African-American, American-Indian, and Arab-American women are disproportionately affected by IBC (1-3). Compared to non-IBC, IBC has a higher incidence of the triple-negative (TN) phenotype for which there are few treatment options. There are currently limited strategies for targeting IBC; thus, IBC patients continue to have worse survival outcomes than non-IBC breast cancer patients. GLI1 (glioma-associated oncogene homolog 1), the terminal effector of the hedgehog (Hh) pathway, has emerged as a potential therapeutic target for TN breast cancers including IBC (4). There is overwhelming evidence for GLI1 activation across many tumor types, including aggressive breast cancers, and its importance for tumor progression. Nuclear expression of GLI1 has been shown to be a strong predictor of poor prognosis in pancreatic cancer and brain gliomas and correlates with aggressiveness in basal-like breast cancer. In our studies, we utilized various automated phenotypic and functional assays (5) to examine the efficacy of GLI antagonists with varying mechanism of action for effects on IBC cell proliferation and growth in 2D and 3D cell culture systems. We are also assessing by high-throughput transcriptome sequencing (RNA-seq) gene expression differences in IBC cell lines after treatment with GLI antagonists. In both our 2D and 3D cell culture systems, TN-IBC cell lines were highly sensitive to two GLI antagonists, JK184 and GANT61. JK184 and GANT61 showed significant but differential effects on TN-IBC cell proliferation, colony formation, cell motility, and spheroid formation. This study was supported in part by Department of Defense award W81WXH-13-1-0141, NIH award P20CA202924, Komen Graduate Training in Disparities Research award GTDR16377604, Developmental Funds from Duke School of Medicine and Duke Cancer Institute (as part of the P30CA014236 and Cancer and Environment Program supported by Mr and Mrs Fred and Alice Stanback P3917733).