Triple-negative breast cancer in African-American women: disparities versus biology

Abstract

Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype that disproportionately affects BRCA1 mutation carriers and young women of African origin. There is evidence that African-American women with TNBC have worse clinical outcomes than women of European descent. However, it is unclear whether survival differences persist after adjusting for disparities in access to health-care treatment, co-morbid disease and income. It remains controversial whether TNBC in African-American women is a molecularly distinct disease or whether African-American women have a higher incidence of aggressive biology driven by disparities: there is evidence in support of both. Understanding the relative contributions of biology and disparities is essential for improving the poor survival rate of African-American women with TNBC.

Figure 1. TNBC in African-American compared with European-American women

a| Age-related incidence of triple-negative breast cancer (TNBC) by race, shown as a percentage of overall breast cancer incidence. b | Survival of African-American women based on breast cancer subtype (oestrogen receptor (ER)⁺, progesterone receptor (PR)⁺, ERBB2⁻ versus ER⁻, PR⁻, ERBB2⁻). c | TNBC survival rate based on race. d | Adjusted odds ratios (ORs) for race (African Americans compared with European Americans) in the Atlanta study. Data for parts a–d are derived from Lund et al. with kind permission from Springer Science and Business Media. CI, confidence interval.

Figure 2. Proposed model of how disparities might drive signalling pathways associated with aggressive biology in TNBC

Disparities in income, lack of access to fresh vegetables and healthy food, unsafe neighbourhoods, and lack of exercise can promote co-morbid diseases such as obesity and diabetes, which in turn may drive phosphoprotein signalling pathways associated with aggressive biology in triple-negative breast cancer (TNBC). Obesity and diabetes result in increased levels of circulating insulin and tissue cytokines, such as interleukin-6 (IL-6), tumour necrosis factor (TNF), leptin, chemokine (C-C motif) ligand 2 (CCL2) and transforming growth factor-β (TGFβ), which activate signalling networks that are known to promote epithelial cell proliferation and genomic instability, including PI3K–AKT, signal transducer and activator of transcription 3 (STAT3)–nuclear factor-κB (NF-κB), WNT–microRNA 34 (miR34)–p53, and Aurora A–polo-like kinase (PLK)^,–,. Obesity and accompanying tissue inflammation increases tissue factors, such as hypoxia-inducible factor 1α (HIF1α), that promote angiogenesis and contribute to aggressive biology. Recent studies provide evidence that chronic tissue inflammation and cyclooxygenase 2 (COX2) activation promote changes in collagen structure that result in the activation of focal adhesion kinase (FAK) and AKT network signalling^,.

Figure 3. Proposed model of genetic and epigenetic mechanisms that link unique DNA sequences and disparities with genomic instability, loss of BRCA1 function and aggressive TNBC biology in women of African descent

Over 60% of Ashkenazi Jewish women with triple-negative breast cancer (TNBC) have a mutation in BRCA1. By contrast, less than 20–25% of African-American women with TNBC have a germline DNA mutation. Although many sequence variations of BRCA1 have been found in women of African descent, only a small number of the mutations are protein truncating^–, and these protein-truncating mutations occur in women of African origin at a lower rate than is observed in women of European descent. On-going studies are testing for germline mutations in other genes that regulate BRCA1-associated DNA repair (for example, partner and localizer of BRCA2 (PALB2)) and/or signalling pathways that promote epigenetic loss of BRCA1 function. As the Black Women’s Health Study matures, it is anticipated that genome-wide association studies focusing on women of African ancestry will provide important insights into the genetic basis of TNBC in African-American women. Active areas of research aim to link disparities in access, environmental exposures, neighbourhood safety and obesity with epigenetic mechanisms that promote genomic instability. These emerging areas of research have important potential to identify important epigenetic mechanisms that link disparities with genomic instability. For example, emerging data indicate that low vitamin D levels may affect DNA repair. African-American women have low vitamin D levels owing to increased skin pigmentation^,; lack of safe neighbourhoods further contributes to low vitamin D levels. Blue boxes: strong mechanistic evidence exists in TNBC, but specifically linking this evidence with TNBC in women of African descent is a work in progress. Tan boxes: areas of on-going investigation for which published data are currently weak or lacking. EZH2, enhancer of zeste homologue 2; IL-6, interleukin-6; miRNA, microRNA; SNP, single-nucleotide polymorphism; STAT3, signal transducer and activator of transcription 3.

Figure 4. Proposed model depicting the intersection of disparities and aggressive biology in African-American women with TNBC

Lack of access to health care and cultural barriers result in delays in diagnosis, delays in treatment, lack of completion of therapy and lack of follow-up for screening tests and treatment, culminating in women presenting with breast cancer at an advanced stage and having poor survival rates. Income inequality results in unequal health insurance and lack of access to genetic testing and state-of-the-art screening for triple-negative breast cancer (TNBC), such as breast magnetic resonance imaging (MRI). Co-morbid diseases such as obesity, diabetes and hypertension complicate therapy and can result in treatment delays. Obesity increases tissue inflammation and the production of tissue cytokines and growth factors that promote aggressive cancer biology. Signalling networks activated by insulin, such as AKT–mTOR, are associated with aggressive cancer biology. Unsafe neighbourhoods and an unequal burden of environmental exposures contribute to stress, lack of access to healthy food (food deserts, which in turn promotes obesity), lack of exercise and exposure to carcinogens and heavy metals (such as cadmium, lead and arsenic) that are thought to promote abnormal imprinting and epigenetic changes^–, which in turn may promote aggressive biology. EMT, epithelial–mesenchymal transition.