Abstract B48: Clues to the causes of the abundance of triple-negative breast cancer in women of African descent

Abstract

Abstract Background: Triple negative breast cancer (TNBC) is over-represented in indigenous African women and in women of African descent. The majority of women diagnosed with breast cancer in Nigeria, Uganda and Kenya have TNBC. Studies of TNBC in the US consistently report the percentage of TNBC to be 10-24% greater in African-Americans (AA) than in Caucasians (C). The abundance of TNBCs in both African and African-American women has yet to be explained and the incidence rates suggest that there may be a genetic predisposition to this particularly aggressive form of breast cancer. Methods: Epithelial cell lines were established from normal, healthy breast tissue donated to the Susan G. Komen for the Cure® Tissue Bank at the IU Simon Cancer Center. Six cell lines from AA donors were matched on the basis of age, menopausal status and Gail-risk score to six cell lines from C donors. RNA was extracted from the cells and gene expression assayed using the Illumina HumanWG6 v3 chip. Significant differences in gene expression were identified using PADE (PAirwise Differential Expression; Expression Analysis, Durham, NC). Results: 1552 genes were differentially expressed (p≤ 0.05). The largest number of genes over-expressed in AAs mapped to the long arm of chromosome 1. Copy number gains have been observed in this region in multiple TNBC data sets. Many of these genes are in the 1q21 region, a region frequently rearranged in epithelial tumors as well as soft tissue and bone. Analysis of differentially expressed genes using MetaCore from Thomson Reuters revealed that the over-expressed genes are responsible for skin development, cell adhesion/cell junctions, and functions of the innate immune system. Pattern recognition is in the vanguard of the innate immune system. The pattern recognition pathways mediated by RAGE (receptor for advanced glycation end products) and the Toll-like receptors are activated in the normal AA epithelium. The expression of genes in these pathways, specifically S100A12, S100A8, S110A9, and TLR5, is known to increase in the presence of Salmonella and Shigella. MDA5 recognizes rotavirus infection. LYST and DUSP4 are active in the control of Leishmania infection. LCN2 disrupts iron acquisition, which protects against a number of pathogens including Salmonella, Klebsiella and mycobacteria. Conclusions: The results of the above gene expression analysis are best understood in light of our recently published findings using these same cells (Sauder et al, BMC Cell Biology, 2014). Epithelial cells grown from mammary explant culture are basal-like and phenotypically plastic. They can assume a wide range of cell types depending on the cues provided by the microenvironment. When grown in basement membrane matrix or on human dermal fibroblasts, these cells produce a stratified squamous epithelium. Although the cells used for the gene expression analysis were grown in plastic tissue culture flasks and grew as a monotonous monolayer, the data suggest that they are, to some extent, transcriptionally “squamous”. For example, they express involucrin and the genes that code for the corneodesmosome proteins: corneodesmin, desmoglein and desmocollin. The skin of humans living in sub-Saharan Africa has evolved to provide optimal barrier protection. It specifically protects against water loss and, pathogenic microorganisms and parasites. Mammary glands are ectodermal appendages of the epithelium and they may share similar immune defense mechanisms. The increased expression of genes involved in innate immunity in AA breast epithelial cells is of significant interest. We hypothesize that a subclinical, chronic inflammatory state is incited within basal breast cells in response to a pathogen that is endemic to Africa and overrepresented in low income communities in the US. This persistent and unresolved innate immunity predates the development of TNBC and can thus participate in its initiation and promotion. Citation Format: Candice A.M. Sauder, Jillian E. Koziel, MiRan Choi, Brittney-Shea Herbert, Susan E. Clare. Clues to the causes of the abundance of triple-negative breast cancer in women of African descent. [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 B48.