Multiethnic Triple Negative Breast Cancer Comparisons Of Gene Expression Shows Enrichment Of Distinct Pathways In Aldh1+Subpopulations Compared To Cd44+/Cd24-/Epcam+

Triple negative breast cancers are a heterogeneous group with diverse, usually poorer survival outcomes and are more prevalent in individuals of African descent. Given the 8-12% higher mortality in breast cancers in individuals of African descent, we set out to identify differences in pathway enrichment in patients with TNBC of Caucasian, African American, and African (Ghanaian) ethnicity. Moreover, we analyzed subpopulations of cells previously found to exhibit stem-like characteristics of self-renewal, within each tumor in order delineate the heterogeneity of gene expression patterns also in different subpopulations of cells within tumors of patients of diverse ethnicities. Based on previous work, we hypothesized that there are distinct sub populations of rare cells, which exhibit distinct signaling pathway enrichment that may confer to TNBCs their highly metastatic and drug resistant characteristics. We developed PDX models from TNBC of 5 Ghanaian, 5 African American and 5 Caucasian patients. We collected bulk cells from the PDXs and used fluorescence-activated cell sorting (FACS) to select and collect ALDH+ cells and CD24-CD44+EpCAM+ (CD44+) cells. We extracted RNA from the sorted cell populations and performed RNA-sequencing using the Illumina Next Generation Sequencing platform. Our results showed that the bulk, ALDH1+ and CD44+ populations within each tumor segregate closely together, and we noted no distinct ethnic separation when we performed the analyses either of the bulk or special subpopulations. Upon centering on the mean for each sample in each tumor, thereby abrogating differences between individual tumors, we observe a significant separation between the ALDH1+ and the CD44+/CD24- sub populations. In particular, the following pathways are most differentially enriched in these subpopulations. The numbers between parentheses indicate the numbers of genes significantly altered that contribute to each pathway. ALDH1+ : Wnt (10), MAPK (13), axon guidance (6), GnRH signaling (7), TGFbeta (9), endocytosis(5) CD44+/CD24-/EpCAM+: tRNA synthesis (5), N-glycan biosynthesis (7), RNA degradation (6) We are focusing our experiments on verifying whether the above pathways are indeed active in these subpopulations and we are exploring their biological significance with regards to tumor growth and metastases. Although we did not detect any specific clustering of tumors by ethnicity, our work suggests the presence of an ALDH1+ subpopulation of cells that exhibit characteristic enrichment of pathways distinct from those enriched in CD44+/CD24-/EpCAM+ cells. Citation Format: Evelyn M. Jiagge, Qingxuan Song, Shukmei Wong, Tahra Luther, Michele Dziubinski, Shawn Clouthier, Sean McDermott, Lisa Newman, John Carpten, Jun Li, Max WIcha, Sofia Merajver. Multiethnic triple negative breast cancer comparisons of gene expression shows enrichment of distinct pathways in ALDH1+ subpopulations compared to CD44+/CD24-/EpCAM+. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1518. doi:10.1158/1538-7445.AM2015-1518