Molecular phenotypes in triple negative breast cancer from African American patients suggest targets for therapy

Abstract

Triple negative breast cancer (TNBC) is characterized by high proliferation, poor differentiation and a poor prognosis due to high rates of recurrence. Despite lower overall incidence African American (AA) patients suffer from higher breast cancer mortality in part due to the higher proportion of TNBC cases among AA patients compared to European Americans (EA). It was recently shown that the clinical heterogeneity of TNBC is reflected by distinct transcriptional programs with distinct drug response profiles in preclinical models. In this study, gene expression profiling and immunohistochemistry were used to elucidate potential differences between TNBC tumors of EA and AA patients on a molecular level. In a retrospective cohort of 136 TNBC patients, a major transcriptional signature of proliferation was found to be significantly upregulated in samples of AA ethnicity. Furthermore, transcriptional profiles of AA tumors showed differential activation of insulin-like growth factor 1 (IGF1) and a signature of BRCA1 deficiency in this cohort. Using signatures derived from the meta-analysis of TNBC gene expression carried out by Lehmann et al., tumors from AA patients were more likely of basal-like subtypes whereas transcriptional features of many EA samples corresponded to mesenchymal-like or luminal androgen receptor driven subtypes. These results were validated in The Cancer Genome Atlas mRNA and protein expression data, again showing enrichment of a basal-like phenotype in AA tumors and mesenchymal subtypes in EA tumors. In addition, increased expression of VEGF-activated genes together with elevated microvessel area determined by the AQUA method suggest that AA patients exhibit higher tumor vascularization. This study confirms the existence of distinct transcriptional programs in triple negative breast cancer in two separate cohorts and that these programs differ by racial group. Differences in TNBC subtypes and levels of tumor angiogenesis in AA versus EA patients suggest that targeted therapy choices should be considered in the context of race.

Figure 1. Differential projection scores on principal component 4 by ethnicity.

Figure 2. Association of ethnicity with TNBC subtypes .

Correlations of gene expression with the mesenchymal stem cell (A), luminal androgen receptor positive (B) and basal 1 (C) subtypes were compared between African American (AA) and European American (EA) patient samples.

Figure 3. Associations of ethnicity with published gene expression signatures.

Signatures of (A) BRCA1 deficiency (B) genomic grade and (C) IGF1 ligand activation were compared between African American (AA) and European American (EA) patient samples.

Figure 4. Representative histospots depicting microvessel area (MVA) and expression of angiogenesis markers.

Panels (A) and (B) show cytokeratin staining for determination of the tumor area in red, DAPI-stained nuclei in blue and CD31-positive microvessel area in green. Panel A depicts a representative histospot from a European American sample, panel B shows a representative African American sample. (C) Proportion of African American and European American patients with large microvessel area (more than 0.6%, hatched bars) (D) Expression ranks of 11 VEGF-activated genes in African American and European American samples.