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.
Subscribe to Journal
Get full journal access for 1 year
only $4.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Foulkes, W. D., Smith, I. E. & Reis-Filho, J. S. Triple-negative breast cancer. N. Engl. J. Med. 363, 1938–1948 (2010).
Sorlie, T. et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc. Natl Acad. Sci. USA 98, 10869–10874 (2001).
Carey, L. A. et al. Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study. JAMA 295, 2492–2502 (2006).
Lund, M. J. et al. Race and triple negative threats to breast cancer survival: a population-based study in Atlanta, GA. Breast Cancer Res. Treat. 113, 357–370 (2009).
Bauer, K. R., Brown, M., Cress, R. D., Parise, C. A. & Caggiano, V. Descriptive analysis of estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and HER2-negative invasive breast cancer, the so-called triple-negative phenotype: a population-based study from the California cancer registry. Cancer 109, 1721–1728 (2007).
Albain, K. S., Unger, J. M., Crowley, J. J., Coltman, C. A. Jr & Hershman, D. L. Racial disparities in cancer survival among randomized clinical trials patients of the Southwest Oncology Group. J. Natl Cancer Inst. 101, 984–992 (2009).
Woodward, W. A. et al. African-American race is associated with a poorer overall survival rate for breast cancer patients treated with mastectomy and doxorubicin-based chemotherapy. Cancer 107, 2662–2668 (2006).
Shen, Y. et al. Are there racial differences in breast cancer treatments and clinical outcomes for women treated at M. D. Anderson Cancer Center? Breast Cancer Res. Treat. 102, 347–356 (2007).
Dawood, S. et al. Triple receptor-negative breast cancer: the effect of race on response to primary systemic treatment and survival outcomes. J. Clin. Oncol. 27, 220–226 (2009).
Dean-Colomb, W. et al. Transcriptional profiles of triple receptor-negative breast cancer: are Caucasian, Hispanic, and African- American women different? J. Clin. Oncol. 26, S22014 (2008).
Vona-Davis, L. & Rose, D. P. The influence of socioeconomic disparities on breast cancer tumor biology and prognosis: a review. J. Womens Health (Larchmt) 18, 883–893 (2009).
Danforth, D. N. Jr Disparities in breast cancer outcomes between Caucasian and African American women: a model for describing the relationship of biological and nonbiological factors. Breast Cancer Res. 15, 208 (2013).
Perou, C. M. et al. Distinctive gene expression patterns in human mammary epithelial cells and breast cancers. Proc. Natl Acad. Sci. USA 96, 9212–9217 (1999).
Perou, C. M. et al. Molecular portraits of human breast tumours. Nature 406, 747–752 (2000).
Morris, G. J. et al. Differences in breast carcinoma characteristics in newly diagnosed African-American and Caucasian patients: a single-institution compilation compared with the National Cancer Institute's Surveillance, Epidemiology, and End Results database. Cancer 110, 876–884 (2007).
Stead, L. A. et al. Triple-negative breast cancers are increased in black women regardless of age or body mass index. Breast Cancer Res. 11, R18 (2009).
Stark, A. et al. African ancestry and higher prevalence of triple-negative breast cancer: findings from an international study. Cancer 116, 4926–4932 (2010).
Fregene, A. & Newman, L. A. Breast cancer in sub-Saharan Africa: how does it relate to breast cancer in African-American women? Cancer 103, 1540–1550 (2005).
Boyle, P. Triple-negative breast cancer: epidemiological considerations and recommendations. Ann. Oncol. 23 (Suppl. 6), vi7–vi12 (2012).
Huo, D. et al. Population differences in breast cancer: survey in indigenous African women reveals over-representation of triple-negative breast cancer. J. Clin. Oncol. 27, 4515–4521 (2009).
McCormack, V. A. et al. Breast cancer receptor status and stage at diagnosis in over 1,200 consecutive public hospital patients in Soweto, South Africa: a case series. Breast Cancer Res. 15, R84 (2013).
Chlebowski, R. T. et al. Ethnicity and breast cancer: factors influencing differences in incidence and outcome. J. Natl Cancer Inst. 97, 439–448 (2005).
Bradley, C. J., Given, C. W. & Roberts, C. Race, socioeconomic status, and breast cancer treatment and survival. J. Natl Cancer Inst. 94, 490–496 (2002).
Ayanian, J. Z., Kohler, B. A., Abe, T. & Epstein, A. M. The relation between health insurance coverage and clinical outcomes among women with breast cancer. N. Engl. J. Med. 329, 326–331 (1993).
McWhorter, W. P. & Mayer, W. J. Black/white differences in type of initial breast cancer treatment and implications for survival. Am. J. Public Health 77, 1515–1517 (1987).
Furberg, H., Millikan, R., Dressler, L., Newman, B. & Geradts, J. Tumor characteristics in African American and white women. Breast Cancer Res. Treat. 68, 33–43 (2001).
Servick, K. Breast cancer: a world of differences. Science 343, 1452–1453 (2014).
Newman, L. A. et al. Meta-analysis of survival in African American and white American patients with breast cancer: ethnicity compared with socioeconomic status. J. Clin. Oncol. 24, 1342–1349 (2006).
Hall, J. M. et al. Linkage of early-onset familial breast cancer to chromosome 17q21. Science 250, 1684–1689 (1990).
Yoshida, K. & Miki, Y. Role of BRCA1 and BRCA2 as regulators of DNA repair, transcription, and cell cycle in response to DNA damage. Cancer Sci. 95, 866–871 (2004).
Antoniou, A. C. & Easton, D. F. Models of genetic susceptibility to breast cancer. Oncogene 25, 5898–5905 (2006).
Mavaddat, N. et al. Pathology of breast and ovarian cancers among BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Cancer Epidemiol. Biomarkers Prev. 21, 134–147 (2012).
Nanda, R. et al. Genetic testing in an ethnically diverse cohort of high-risk women: a comparative analysis of BRCA1 and BRCA2 mutations in American families of European and African ancestry. JAMA 294, 1925–1933 (2005).
Olopade, O. I. et al. Breast cancer genetics in African Americans. Cancer 97, 236–245 (2003).
Greenup, R. et al. Prevalence of BRCA mutations among women with triple-negative breast cancer (TNBC) in a genetic counseling cohort. Ann. Surg. Oncol. 20, 3254–3258 (2013).
Oluwagbemiga, L. A., Oluwole, A. & Kayode, A. A. Seventeen years after BRCA1: what is the BRCA mutation status of the breast cancer patients in Africa? — a systematic review. SpringerPlus 1, 83 (2012).
Szabo, C. I. & King, M. C. Population genetics of BRCA1 and BRCA2. Am. J. Hum. Genet. 60, 1013–1020 (1997).
Yawitch, T. M., van Rensburg, E. J., Mertz, M. & Falkson, C. I. Absence of commonly recurring BRCA1 mutations in black South African women with breast cancer. S. Afr. Med. J. 90, 788 (2000).
Gao, Q. et al. Protein truncating BRCA1 and BRCA2 mutations in African women with pre-menopausal breast cancer. Hum. Genet. 107, 192–194 (2000).
Fackenthal, J. D. et al. Complete allelic analysis of BRCA1 and BRCA2 variants in young Nigerian breast cancer patients. J. Med. Genet. 42, 276–281 (2005).
Zhang, B. et al. Evidence for an ancient BRCA1 mutation in breast cancer patients of Yoruban ancestry. Fam. Cancer 8, 15–22 (2009).
Zhang, J., Fackenthal, J. D., Huo, D., Zheng, Y. & Olopade, O. I. Searching for large genomic rearrangements of the BRCA1 gene in a Nigerian population. Breast Cancer Res. Treat. 124, 573–577 (2010).
Churpek, J. E. et al. Inherited mutations in breast cancer genes in African-American breast cancer patients revealed by targeted genomic capture and next-generation sequencing. J. Clin. Oncol. 31, CRA1501 (2013).
Antoniou, A. C. et al. Breast-cancer risk in families with mutations in PALB2. N. Engl. J. Med. 371, 497–506 (2014).
Zheng, Y., Zhang, J., Niu, Q., Huo, D. & Olopade, O. I. Novel germline PALB2 truncating mutations in African American breast cancer patients. Cancer 118, 1362–1370 (2012).
Haiman, C. A. et al. A common variant at the TERT-CLPTM1L locus is associated with estrogen receptor–negative breast cancer. Nature Genet. 43, 1210–1214 (2011).
Ruiz-Narvaez, E. A. et al. Polymorphisms in the TOX3/LOC643714 locus and risk of breast cancer in African-American women. Cancer Epidemiol. Biomarkers Prev. 19, 1320–1327 (2010).
Palmer, J. R. et al. Genetic susceptibility loci for subtypes of breast cancer in an African American population. Cancer Epidemiol. Biomarkers Prev. 22, 127–134 (2013).
Field, L. A. et al. Identification of differentially expressed genes in breast tumors from African American compared with Caucasian women. Cancer 118, 1334–1344 (2012).
Martin, D. N. et al. Differences in the tumor microenvironment between African-American and European-American breast cancer patients. PLoS ONE 4, e4531 (2009).
Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nature 490, 61–70 (2012).
Stewart, P. A., Luks, J., Roycik, M. D., Sang, Q. X. & Zhang, J. Differentially expressed transcripts and dysregulated signaling pathways and networks in African American breast cancer. PLoS ONE 8, e82460 (2013).
Sturtz, L. A., Melley, J., Mamula, K., Shriver, C. D. & Ellsworth, R. E. Outcome disparities in African American women with triple negative breast cancer: a comparison of epidemiological and molecular factors between African American and Caucasian women with triple negative breast cancer. BMC Cancer 14, 62 (2014).
Lindner, R. et al. Molecular phenotypes in triple negative breast cancer from African American patients suggest targets for therapy. PLoS ONE 8, e71915 (2013).
Kleer, C. G. et al. EZH2 is a marker of aggressive breast cancer and promotes neoplastic transformation of breast epithelial cells. Proc. Natl Acad. Sci. USA 100, 11606–11611 (2003).
De Brot, M., Rocha, R. M., Soares, F. A. & Gobbi, H. Prognostic impact of the cancer stem cell related markers ALDH1 and EZH2 in triple negative and basal-like breast cancers. Pathology 44, 303–312 (2012).
Hussein, Y. R. et al. Clinical and biological relevance of enhancer of zeste homolog 2 in triple-negative breast cancer. Hum. Pathol. 43, 1638–1644 (2012).
Gonzalez, M. E. et al. Histone methyltransferase EZH2 induces Akt-dependent genomic instability and BRCA1 inhibition in breast cancer. Cancer Res. 71, 2360–2370 (2011).
Pang, J. et al. Invasive breast carcinomas in Ghana: high frequency of high grade, basal-like histology and high EZH2 expression. Breast Cancer Res. Treat. 135, 59–66 (2012).
Pietersen, A. M. et al. EZH2 and BMI1 inversely correlate with prognosis and TP53 mutation in breast cancer. Breast Cancer Res. 10, R109 (2008).
King, T. D., Suto, M. J. & Li, Y. The Wnt/β-catenin signaling pathway: a potential therapeutic target in the treatment of triple negative breast cancer. J. Cell Biochem. 113, 13–18 (2012).
Wend, P. et al. WNT10B/β-catenin signalling induces HMGA2 and proliferation in metastatic triple-negative breast cancer. EMBO Mol. Med. 5, 264–279 (2013).
Getz, J. et al. Differential gene expression in key oncolytic pathways between node-matched Caucasian-American, African-American, and East African triple-negative breast cancer patients. Cancer Res. 74, 2368 (2014).
Al-Hajj, M., Wicha, M. S., Benito-Hernandez, A., Morrison, S. J. & Clarke, M. F. Prospective identification of tumorigenic breast cancer cells. Proc. Natl Acad. Sci. USA 100, 3983–3988 (2003).
Ginestier, C. et al. ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell 1, 555–567 (2007).
Fillmore, C. M. & Kuperwasser, C. Human breast cancer cell lines contain stem-like cells that self-renew, give rise to phenotypically diverse progeny and survive chemotherapy. Breast Cancer Res. 10, R25 (2008).
Nalwoga, H., Arnes, J. B., Wabinga, H. & Akslen, L. A. Expression of aldehyde dehydrogenase 1 (ALDH1) is associated with basal-like markers and features of aggressive tumours in African breast cancer. Br. J. Cancer 102, 369–375 (2010).
Silber, J. H. et al. Characteristics associated with differences in survival among black and white women with breast cancer. JAMA 310, 389–397 (2013).
Black, S. A. Diabetes, diversity, and disparity: what do we do with the evidence? Am. J. Public Health 92, 543–548 (2002).
Hood, E. Dwelling disparities: how poor housing leads to poor health. Environ. Health Perspect. 113, A310–A317 (2005).
Lee, E. et al. Characteristics of triple-negative breast cancer in patients with a BRCA1 mutation: results from a population-based study of young women. J. Clin. Oncol. 29, 4373–4380 (2011).
Pierobon, M. & Frankenfeld, C. L. Obesity as a risk factor for triple-negative breast cancers: a systematic review and meta-analysis. Breast Cancer Res. Treat. 137, 307–314 (2013).
Kwan, M. L. et al. Epidemiology of breast cancer subtypes in two prospective cohort studies of breast cancer survivors. Breast Cancer Res. 11, R31 (2009).
Creighton, C. J. et al. Residual breast cancers after conventional therapy display mesenchymal as well as tumor-initiating features. Proc. Natl Acad. Sci. USA 106, 13820–13825 (2009).
Hartman, Z. C. et al. Growth of triple-negative breast cancer cells relies upon coordinate autocrine expression of the proinflammatory cytokines IL-6 and IL-8. Cancer Res. 73, 3470–3480 (2013).
Hall, I. J., Moorman, P. G., Millikan, R. C. & Newman, B. Comparative analysis of breast cancer risk factors among African-American women and White women. Am. J. Epidemiol. 161, 40–51 (2005).
Shinde, S. S. et al. Higher parity and shorter breastfeeding duration: association with triple-negative phenotype of breast cancer. Cancer 116, 4933–4943 (2010).
Palmer, J. R. et al. Parity and lactation in relation to estrogen receptor negative breast cancer in African American women. Cancer Epidemiol. Biomarkers Prev. 20, 1883–1891 (2011).
Lyons, T. R. et al. Postpartum mammary gland involution drives progression of ductal carcinoma in situ through collagen and COX-2. Nature Med. 17, 1109–1115 (2011).
Conklin, M. W. et al. Aligned collagen is a prognostic signature for survival in human breast carcinoma. Am. J. Pathol. 178, 1221–1232 (2011).
Lu, P., Weaver, V. M. & Werb, Z. The extracellular matrix: a dynamic niche in cancer progression. J. Cell Biol. 196, 395–406 (2012).
Gonzalez-Suarez, I. et al. A new pathway that regulates 53BP1 stability implicates cathepsin L and vitamin D in DNA repair. EMBO J. 30, 3383–3396 (2011).
Harris, S. S. & Dawson-Hughes, B. Seasonal changes in plasma 25-hydroxyvitamin D concentrations of young American black and white women. Am. J. Clin. Nutr. 67, 1232–1236 (1998).
Clemens, T. L., Adams, J. S., Henderson, S. L. & Holick, M. F. Increased skin pigment reduces the capacity of skin to synthesise vitamin D3. Lancet 1, 74–76 (1982).
Lancaster, K. J. & Bermudez, O. I. Beginning a discussion of nutrition and health disparities. Am. J. Clin. Nutr. 93, 1161S–1162S (2011).
Murphy, S. K., Huang, Z. & Hoyo, C. Differentially methylated regions of imprinted genes in prenatal, perinatal and postnatal human tissues. PLoS ONE 7, e40924 (2012).
Ho, S. M. et al. Environmental epigenetics and its implication on disease risk and health outcomes. ILAR J. 53, 289–305 (2012).
Pozharny, Y., Lambertini, L., Clunie, G., Ferrara, L. & Lee, M. J. Epigenetics in women's health care. Mt. Sinai J. Med. 77, 225–235 (2010).
Smeester, L. et al. Imprinted genes and the environment: links to the toxic metals arsenic, cadmium, lead and mercury. Genes (Basel) 5, 477–496 (2014).
This work was supported by US National Institutes of Health/National Cancer Institute (NIH/NCI) grants R01CA155664, R01CA158668, R01CA170851 (to V.L.S.) and CA155664-03S1 (to C.S.), a Susan G. Komen Breast Promise Award (KG091020; to V.L.S.) and a V-Foundation Award (to V.L.S.). This work was also funded by a gift from F. Stanback and A. Stanback. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
The authors declare no competing financial interests.
About this article
Cite this article
Dietze, E., Sistrunk, C., Miranda-Carboni, G. et al. Triple-negative breast cancer in African-American women: disparities versus biology. Nat Rev Cancer 15, 248–254 (2015). https://doi.org/10.1038/nrc3896
Nature Communications (2021)
Genetic variation associated with thyroid autoimmunity shapes the systemic immune response to PD-1 checkpoint blockade
Nature Communications (2021)
Scientific Reports (2021)
Breast Cancer Research and Treatment (2021)