Abstract
Purpose
Triple-negative breast cancer (TNBC) is an aggressive subtype most prevalent among women of Western Sub-Saharan African ancestry. It accounts for 15–25% of African American (AA) breast cancers (BC) and up to 80% of Ghanaian breast cancers, thus contributing to outcome disparities in BC for black women. The aggressive biology of TNBC has been shown to be regulated partially by breast cancer stem cells (BCSC) which mediate tumor recurrence and metastasis and are more abundant in African breast tumors.
Methods
We studied the biological differences between TNBC in women with African ancestry and those of Caucasian women by comparing the gene expression of the BCSC. From low-passage patient derived xenografts (PDX) from Ghanaian (GH), AA, and Caucasian American (CA) TNBCs, we sorted for and sequenced the stem cell populations and analyzed for differential gene enrichment.
Results
In our cohort of TNBC tumors, we observed that the ALDH expressing stem cells display distinct ethnic specific gene expression patterns, with the largest difference existing between the GH and AA ALDH+ cells. Furthermore, the tumors from the women of African ancestry [GH/AA] had ALDH stem cell (SC) enrichment for expression of immune related genes and processes. Among the significantly upregulated genes were CD274 (PD-L1), CXCR9, CXCR10 and IFI27, which could serve as potential drug targets.
Conclusions
Further exploration of the role of immune regulated genes and biological processes in BCSC may offer insight into developing novel approaches to treating TNBC to help ameliorate survival disparities in women with African ancestry.
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Abbreviations
- AA:
-
African Americans
- ALDH:
-
Aldehyde dehydrogenase
- BC:
-
Breast cancer
- BCSC:
-
Breast cancer stem cells
- CA:
-
Caucasian Americans
- FACS:
-
Fluorescent activated cell sorting
- GH:
-
Ghanaian
- GO:
-
Gene Ontology Consortium
- H&E:
-
Hematoxylin and eosin
- KATH:
-
Komfo Anokye Teaching Hospital
- KEGG:
-
Kyoto Encyclopedia of Genes and Genomes
- PCA:
-
Principal component analysis
- TNBC:
-
Triple-negative breast cancer
- UM:
-
The University of Michigan
- WSSA:
-
Western sub-Saharan Africans
References
Jiagge E, Chitale D, Newman LA (2018) Triple-negative breast cancer, stem cells, and African ancestry. Am J Pathol 188(2):271–279
Stark A et al (2010) African ancestry and higher prevalence of triple-negative breast cancer: findings from an international study. Cancer 116(21):4926–4932
Schwartz T et al (2013) Expression of aldehyde dehydrogenase 1 as a marker of mammary stem cells in benign and malignant breast lesions of Ghanaian women. Cancer 119(3):488–494
Jiagge E et al (2016) Comparative analysis of breast cancer phenotypes in African American, White American, and West versus East African patients: correlation between African ancestry and triple-negative breast cancer. Ann Surg Oncol 23:3843–3849
Jiagge E et al (2018) Androgen receptor and ALDH1 expression among internationally diverse patient populations. J Glob Oncol 4:1–8
Jiagge E et al (2016) Breast cancer and African Ancestry: lessons learned at the 10-year anniversary of the Ghana-Michigan Research Partnership and International Breast Registry. J Glob Oncol 2(5):302–310
Newman LA et al (2006) Meta-analysis of survival in African American and white American patients with breast cancer: ethnicity compared with socioeconomic status. J Clin Oncol 24(9):1342–1349
Newman LA et al (2019) Hereditary susceptibility for triple negative breast cancer associated with Western Sub-Saharan African ancestry: results from an International Surgical Breast Cancer Collaborative. Ann Surg 270(3):484–492
Carey LA et al (2007) The triple negative paradox: primary tumor chemosensitivity of breast cancer subtypes. Clin Cancer Res 13(8):2329–2334
Carey LA et al (2006) Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study. JAMA 295(21):2492–2502
Charafe-Jauffret E et al (2009) Breast cancer cell lines contain functional cancer stem cells with metastatic capacity and a distinct molecular signature. Cancer Res 69(4):1302–1313
Dontu G et al (2003) In vitro propagation and transcriptional profiling of human mammary stem/progenitor cells. Genes Dev 17(10):1253–1270
Ginestier C et al (2007) ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell 1(5):555–567
Nalwoga H et al (2010) 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(2):369–375
Dave B, Chang J (2009) Treatment resistance in stem cells and breast cancer. J Mammary Gland Biol Neoplasia 14(1):79–82
Li X et al (2008) Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy. J Natl Cancer Inst 100(9):672–679
Al-Hajj M et al (2003) Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA 100(7):3983–3988
Perrone G et al (2012) In situ identification of CD44+/CD24- cancer cells in primary human breast carcinomas. PLoS One 7(9):e43110
Fitzgibbons et al (2013) Template for reporting results of biomarker testing of specimens from patients with carcinoma of the breast. Am Coll Pathologists 138(5):595–601
Draghici S et al (2007) A systems biology approach for pathway level analysis. Genome Res 17(10):1537–1545
Tarca AL et al (2009) A novel signaling pathway impact analysis. Bioinformatics 25(1):75–82
Alexa A, Rahnenfuhrer J, Lengauer T (2006) Improved scoring of functional groups from gene expression data by decorrelating GO graph structure. Bioinformatics 22(13):1600–1607
Szklarczyk D et al (2017) The STRING database in 2017: quality-controlled protein–protein association networks, made broadly accessible. Nucleic Acids Res 45(D1):D362–D368
Ding L et al (2010) Genome remodelling in a basal-like breast cancer metastasis and xenograft. Nature 464(7291):999–1005
du Manoir S et al (2014) Breast tumor PDXs are genetically plastic and correspond to a subset of aggressive cancers prone to relapse. Mol Oncol 8(2):431–443
Kobayashi H et al (2013) Hereditary breast and ovarian cancer susceptibility genes (review). Oncol Rep 30(3):1019–1029
Coles C et al (1992) p53 mutations in breast cancer. Cancer Res 52(19):5291–5298
Witton CJ et al (2003) Expression of the HER1-4 family of receptor tyrosine kinases in breast cancer. J Pathol 200(3):290–297
Yu LY et al (2017) New immunotherapy strategies in breast cancer. Int J Environ Res Public Health 14(1):68
Mittendorf EA et al (2014) PD-L1 expression in triple-negative breast cancer. Cancer Immunol Res 2(4):361–370
Jafarzadeh A et al (2016) Higher circulating levels of chemokine CXCL10 in patients with breast cancer: evaluation of the influences of tumor stage and chemokine gene polymorphism. Cancer Biomark 16(4):545–554
Hendrickx W et al (2017) Identification of genetic determinants of breast cancer immune phenotypes by integrative genome-scale analysis. Oncoimmunology 6(2):e1253654
Jiagge E et al (2016) Comparative analysis of breast cancer phenotypes in African American, White American, and West versus East African patients: correlation between African ancestry and triple-negative breast cancer. Ann Surg Oncol 23(12):3843–3849
Bryc K et al (2015) The genetic ancestry of African Americans, Latinos, and European Americans across the United States. Am J Hum Genet 96(1):37–53
Klemm F, Joyce JA (2015) Microenvironmental regulation of therapeutic response in cancer. Trends Cell Biol 25(4):198–213
Fulton A et al (2006) Prospects of controlling breast cancer metastasis by immune intervention. Breast Dis 26:115–127
Ejaeidi AA et al (2015) Hormone receptor-independent CXCL10 production is associated with the regulation of cellular factors linked to breast cancer progression and metastasis. Exp Mol Pathol 99(1):163–172
Planes-Laine G, Rochigneux P, Bertucci F et al (2019) PD-1/PD-L1 targeting in breast cancer: the first clinical evidences are emerging. A literature review. Cancers (Basel) 11(7):1033. https://doi.org/10.3390/cancers11071033
Yuan C, Liu Z, Yu Q, Wang X, Bian M, Yu Z, Yu J (2019) Expression of PD-1/PD-L1 in primary breast tumours and metastatic axillary lymph nodes and its correlation with clinicopathological parameters. Sci Rep 9(1):14356. https://doi.org/10.1038/s41598-019-50898-3
Coban C et al (2005) Toll-like receptor 9 mediates innate immune activation by the malaria pigment hemozoin. J Exp Med 201(1):19–25
Dobrolecki LE, Airhart SD, Alferez DG, Aparicio S, Behbod F, Bentires-Alj M, Brisken C, Bult CJ, Cai S, Clarke RB, Dowst H, Ellis MJ, Gonzalez-Suarez E, Iggo RD, Kabos P, Li S, Lindeman GJ, Marangoni E, McCoy A, Meric-Bernstam F, Lewis MT (2016) Patient-derived xenograft (PDX) models in basic and translational breast cancer research. Cancer Metastasis Rev 35(4):547–573. https://doi.org/10.1007/s10555-016-9653-x
Dominguez TP, Strong EF, Krieger N, Gillman MW, Rich-Edwards JW (2009) Differences in the self-reported racism experiences of US-born and foreign-born Black pregnant women. Soc Sci Med 69(2):258–265. https://doi.org/10.1016/j.socscimed.2009.03.022
Acknowledgements
Work supported in part by the Komen for the Cure Promise grant (LN, MW, JC), the Breast Cancer Research Foundation (MW, SDM), the Metavivor Foundation (SDM), the Rackham Barbour Scholarship, UM Cancer Center Support Grant P30 CA 046592, and the ULAM In Vivo Animal Core histopathology laboratory.
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Jiagge, E.M., Ulintz, P.J., Wong, S. et al. Multiethnic PDX models predict a possible immune signature associated with TNBC of African ancestry. Breast Cancer Res Treat 186, 391–401 (2021). https://doi.org/10.1007/s10549-021-06097-8
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DOI: https://doi.org/10.1007/s10549-021-06097-8