Abstract A74: Differential Wnt signaling in African American and Caucasian women with triple-negative breast cancer

Abstract

Abstract In the U.S., breast cancer (BC) incidences among African American (AA) and Caucasian (CA) women are similar, however, AA have a significantly higher mortality rate (20%). In addition, AA women often present with tumors at a younger age, with a higher grade/later stage, and are more likely to be diagnosed with the highly aggressive triple-negative breast cancer (TNBC) subtype. Although multiple factors may contribute to the observed health disparities in TNBC, it is essential that we identify the molecular characteristics and underlying biological differences between CA and AA TNBC. We initially conducted a gene expression study using archived formalin-fixed, paraffin-embedded (FFPE) samples obtained from CA and AA women diagnosed with Node 0 TNBC. Briefly; total RNA was isolated from 10 μm scrolls from each FFPE block, cDNA synthesis, and each sample was hybridized to a breast-enriched gene expression array (Affymetrix, BC DSA Research Tool). Expression analysis was conducted using GeneSpring 12.1 analytical software. PCA analysis revealed that the samples clustered well with respect to ethnicity and unsupervised hierarchical clustering analysis resulted in distinct subgroups based on ethnicity. Differentially expressed genes (DEG) from each cohort were selected using ANOVA analysis (fold change > 2.0, p value <.05) followed by the Benjamin/Hochberg for multiple-testing correction. Finally, the DEG was imported into GeneGo MetaCore, which revealed that the majority of functionally enriched pathways were associated with the Wnt/β-catenin signaling pathway in the AA-TNBC cohort. Additionally, TNC, CAV1, TCF4 and FOX03A, genes associated with this pathway, were significantly upregulated in the AA-TNBC cohort. We have thus far validated these findings for CAV1 and FOX03A by qRTPCR, using an independent cohort of Node 0 TNBC FFPE samples from AA and CA women. These observations are being investigated in-vitro, using a multi-ethnic TNBC cell line panel, and siRNA-mediated knockdown of the Wnt-associated genes. The effects will be evaluated through a series of functional assays including proliferation, migration, invasion, apoptosis, and epithelial-mesenchymal transition (EMT). We believe that our observations suggest that the Wnt/β-catenin pathway may contribute to the more aggressive phenotype observed in AA women diagnosed with TNBC. These studies have important implications for further understanding of TNBC and the associated health disparities that exist in AA women diagnosed with this disease; ultimately leading to the development of targeted therapies for treating this aggressive subtype of BC. Citation Format: Julie E. Getz, Davyd B. Teoh, Sara Nasser, Tembe Waibhav, Legendre R. Christophe, Venkata Yellapantula, Mary Ellen Ahearn, Carmen R. Gomez, Merce Jorda, Mark D. Pegram, John D. Carpten, Lisa L. Baumbach. Differential Wnt signaling in African American and Caucasian women with triple-negative breast cancer. [abstract]. In: Proceedings of the Seventh AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 9-12, 2014; San Antonio, TX. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2015;24(10 Suppl):Abstract nr A74.