Abstract C054: Characterizing differences in the chromatin accessibility landscape by donor ancestry in human triple-negative breast cancer cell lines
Authors: Harris Alexandra R. , Koparde Vishal , Panigrahi Gatikrushna , Bailey-Whyte Maeve , Dorsey Tiffany , Ambs Stefan 
Published: January 2023

African American (AA) women are at increased risk of developing and dying from Triple-Negative Breast Cancer (TNBC), an aggressive breast cancer subtype, compared to European American (EA) women in the United States. In addition to social determinants, further investigation into biologic factors that contribute to these disparities is needed to fully understand this multi-factorial problem. In particular, the epigenetics of racial/population diversity and its influence on breast cancer incidence and outcomes remain underexplored. Using ATAC-sequencing, we characterized differences in chromatin accessibility between EA-derived versus AA-derived breast cancer cell lines across a range of breast cancer subtypes. Interestingly, our principal component analysis of the top 50,000 peaks with the most variance revealed separation of chromatin profiles by genetic ancestry specifically in TNBC cell lines (N=10). Digital footprinting analysis of differentially open chromatin regions using TOBIAS revealed significant differences in transcription factor (TF) binding by ancestry (61 TFs with a differential binding score &gt; 0.25 or &lt; -0.25 and FDR &lt; 0.01). AA TNBC cell lines exhibited increased binding of transcription factors associated with epithelial-to-mesenchymal transition (ZEB1, SNAI1, GRHL2), cancer stemness and chemotherapeutic resistance (TFAP2C, NRF1), and others such as KAISO, whose aberrant expression has been previously linked to a distinct biology and poor outcomes in AA breast and prostate cancer patients. Pathway analysis of genes located within promoters of differentially open chromatin regions reveals enrichment of the following KEGG pathways in AA TNBC cells: inflammatory mediator regulation of TRP channels (p-adj = 0.009), Hippo signaling (p-adj = 0.006), Wnt signaling (p-adj = 0.031), and Rap-1 signaling (p-adj = 0.046). Together, these data reveal a differential chromatin landscape associated with the aberrant activity of critical TFs and downstream gene expression changes that may contribute to worsened TNBC biology in women of African ancestry. Additionally, as many of these cell lines are used routinely in biomedical research, these findings also indicate that the ancestral origin of patient derived cell lines matters and may contribute to biologic variation in experimental data, suggesting that inclusion of diversely sourced cell lines should be considered in experimental design.

Citation Format: Alexandra R. Harris, Vishal Koparde, Gatikrushna Panigrahi, Maeve Bailey-Whyte, Tiffany Dorsey, Stefan Ambs. Characterizing differences in the chromatin accessibility landscape by donor ancestry in human triple-negative breast cancer cell lines [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr C054.