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Multiethnic PDX models predict a possible immune signature associated with TNBC of African ancestry

  • Preclinical study
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

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

  1. Jiagge E, Chitale D, Newman LA (2018) Triple-negative breast cancer, stem cells, and African ancestry. Am J Pathol 188(2):271–279

    Article  Google Scholar 

  2. 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

    Article  Google Scholar 

  3. 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

    Article  CAS  Google Scholar 

  4. 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

    Article  Google Scholar 

  5. Jiagge E et al (2018) Androgen receptor and ALDH1 expression among internationally diverse patient populations. J Glob Oncol 4:1–8

    PubMed  Google Scholar 

  6. 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

    Article  Google Scholar 

  7. 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

    Article  Google Scholar 

  8. 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

    Article  Google Scholar 

  9. Carey LA et al (2007) The triple negative paradox: primary tumor chemosensitivity of breast cancer subtypes. Clin Cancer Res 13(8):2329–2334

    Article  CAS  Google Scholar 

  10. Carey LA et al (2006) Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study. JAMA 295(21):2492–2502

    Article  CAS  Google Scholar 

  11. 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

    Article  CAS  Google Scholar 

  12. Dontu G et al (2003) In vitro propagation and transcriptional profiling of human mammary stem/progenitor cells. Genes Dev 17(10):1253–1270

    Article  CAS  Google Scholar 

  13. 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

    Article  CAS  Google Scholar 

  14. 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

    Article  CAS  Google Scholar 

  15. Dave B, Chang J (2009) Treatment resistance in stem cells and breast cancer. J Mammary Gland Biol Neoplasia 14(1):79–82

    Article  Google Scholar 

  16. Li X et al (2008) Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy. J Natl Cancer Inst 100(9):672–679

    Article  CAS  Google Scholar 

  17. Al-Hajj M et al (2003) Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA 100(7):3983–3988

    Article  CAS  Google Scholar 

  18. Perrone G et al (2012) In situ identification of CD44+/CD24- cancer cells in primary human breast carcinomas. PLoS One 7(9):e43110

    Article  CAS  Google Scholar 

  19. 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

  20. Draghici S et al (2007) A systems biology approach for pathway level analysis. Genome Res 17(10):1537–1545

    Article  CAS  Google Scholar 

  21. Tarca AL et al (2009) A novel signaling pathway impact analysis. Bioinformatics 25(1):75–82

    Article  CAS  Google Scholar 

  22. 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

    Article  CAS  Google Scholar 

  23. 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

    Article  CAS  Google Scholar 

  24. Ding L et al (2010) Genome remodelling in a basal-like breast cancer metastasis and xenograft. Nature 464(7291):999–1005

    Article  CAS  Google Scholar 

  25. 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

    Article  Google Scholar 

  26. Kobayashi H et al (2013) Hereditary breast and ovarian cancer susceptibility genes (review). Oncol Rep 30(3):1019–1029

    Article  CAS  Google Scholar 

  27. Coles C et al (1992) p53 mutations in breast cancer. Cancer Res 52(19):5291–5298

    CAS  PubMed  Google Scholar 

  28. Witton CJ et al (2003) Expression of the HER1-4 family of receptor tyrosine kinases in breast cancer. J Pathol 200(3):290–297

    Article  CAS  Google Scholar 

  29. Yu LY et al (2017) New immunotherapy strategies in breast cancer. Int J Environ Res Public Health 14(1):68

    Article  Google Scholar 

  30. Mittendorf EA et al (2014) PD-L1 expression in triple-negative breast cancer. Cancer Immunol Res 2(4):361–370

    Article  CAS  Google Scholar 

  31. 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

    Article  CAS  Google Scholar 

  32. Hendrickx W et al (2017) Identification of genetic determinants of breast cancer immune phenotypes by integrative genome-scale analysis. Oncoimmunology 6(2):e1253654

    Article  Google Scholar 

  33. 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

    Article  Google Scholar 

  34. 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

    Article  CAS  Google Scholar 

  35. Klemm F, Joyce JA (2015) Microenvironmental regulation of therapeutic response in cancer. Trends Cell Biol 25(4):198–213

    Article  Google Scholar 

  36. Fulton A et al (2006) Prospects of controlling breast cancer metastasis by immune intervention. Breast Dis 26:115–127

    Article  CAS  Google Scholar 

  37. 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

    Article  CAS  Google Scholar 

  38. 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

    Article  CAS  Google Scholar 

  39. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. 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

    Article  CAS  Google Scholar 

  41. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. 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

    Article  PubMed  PubMed Central  Google Scholar 

Download references

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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Authors and Affiliations

  1. Henry Ford Cancer Institute/Henry Ford Health System, 2799 W Grand Blvd, Detroit, MI, 48202, USA

    Evelyn M. Jiagge, Sabrina I. Fossi, Jessica M. Bensenhaver, Kurt Fernando & Dhananjay Chitale

  2. Department of Internal Medicine, Michigan Medicine, University of Michigan, 1500 East Medical Center Drive, RCC 7314, Ann Arbor, MI, 48105, USA

    Evelyn M. Jiagge, Peter J. Ulintz, Sean P. McDermott, Sabrina I. Fossi, Max S. Wicha & Sofia D. Merajver

  3. Rogel Cancer Center, University of Michigan, Ann Arbor, MI, 48105, USA

    Evelyn M. Jiagge, Peter J. Ulintz, Tahra K. Suhan, Michele Dziubinski, Jun Li, Max S. Wicha & Sofia D. Merajver

  4. Department of Urology, Michigan Medicine, University of Michigan, Ann Arbor, USA

    Tahra K. Suhan

  5. The Translational Genomics Research Institute, Phoenix, AZ, USA

    Shukmei Wong, Jessica Aldrich, Ahmet Kurdoglu & Jeff M. Trent

  6. Unit for Laboratory Animal Medicine, University of Michigan, Ann Arbor, USA

    Mark J. Hoenerhoff

  7. Komfo Anokye Teaching Hospital, Kumasi, Ghana

    Joseph K. Oppong, Francis Aitpillah, Kyei Ishmael, Ernest Osei-Bonsu, Ernest Adjei & Awuah Baffour

  8. Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    David W. Craig & John D. Carpten

  9. New York-Presbyterian/Weill Cornell Medical Center and Weill Cornell Medicine, New York, NY, USA

    Lisa A. Newman

  10. Michigan Institute for Clinical & Health Research, Ann Arbor, USA

    Barbara Salem

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  1. Evelyn M. Jiagge
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  22. Jun Li
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Correspondence to Evelyn M. Jiagge or Sofia D. Merajver.

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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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