Abstract
Abstract In the U.S., the incidence rates of breast cancer (BC) among Caucasian (CA) women are lower than those of African American (AA), however, AA women have a significantly higher mortality rate. AA women often present at a younger age, with later stage and higher grade tumors. In fact, AA women are 3x more likely to be diagnosed with the more aggressive molecular subtype, triple-negative breast cancer (TNBC), than CA women. Socioeconomic and lifestyle factors may be contributory; however, it is imperative that we investigate the underlying molecular biology that may be the cause of health disparities between AA and CA with TNBC. In this study, gene expression profiling, using the Almac BC DSA Research Tool, was performed on archived FFPE samples, obtained from CA and AA women diagnosed with early stage (Node 0) TNBC. Unsupervised hierarchical clustering revealed a pattern of differential gene expression in the AA cohort compared to CA. Using the TNBC type: A Subtyping Tool for TNBC, we found a distinct distribution pattern of TNBC molecular subtypes in the AA cohort, which was very different than the CA cohort; Basal-like (14%), Immunomodulatory (43%) and Mesenchymal (43%). Gene expression analyses, comparing the AA and CA cohort (fold change > 2.0, p-value <.05), resulted in 190 differentially expressed genes (DEG). Pathway enrichment analysis conducted in MetaCore GeneGo, revealed that the DEGs were over-represented in cytoskeletal remodeling, cell adhesion, tight junctions, and immune response in the AA TNBC cohort. Furthermore, several genes in the Wnt/β-catenin pathways were over-expressed in the top 10-enrichment pathways. We validated our results using RT-qPCR and identified Caveolin-1 (CAV1) as being significantly expressed in the AA-TNBC cohort (p-value 1.22 x 10-05). An independent cohort of FFPE samples, from AA and CA women with early stage TNBC, was used to create a tissue microarray (TMA). Immunohistochemistry results showed no difference in localization of Cav1 between the AA and CA cohorts, however, the AA cohort had significantly higher levels of Cav1 staining (p-value 0.04). Additionally, using RT-qPCR, we demonstrated that CAV1 mRNA was significantly higher in the AA TNBC Cohort (p-value 0.48). Furthermore, endogenous Cav1 was shown to be highly expressed in a cell line panel of TNBC, in particular, those of the mesenchymal and basal-like molecular subtype. Finally, using siRNA, we demonstrated that CAV1 silencing resulted in a significant decrease in cell proliferation, for each of the TNBC cell lines while it showed no effect on the luminal ER+ cell lines. Our combined study results suggest that CAV1 over-expression may be a biological contributor to the observed health disparity between AA women and CA diagnosed with early stage TNBC. Citation Format: Julie E. Getz, Davyd B. Teoh, Sara Nasser, Christophe R. Legendre, Waibhav Tembe, Venkata Yellapantula, Mary Ellen Ahearn, Carmen R. Gomez, Merce Jorda, Shuk Mei Wong, Mark D. Pegram, John D. Carpten, Lisa L. Baumbach-Reardon. High caveolin-1 expression in a cohort of African American women with triple-negative breast cancer. [abstract]. In: Proceedings of the Eighth AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 13-16, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2016;25(3 Suppl):Abstract nr C54.
