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

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

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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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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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Keywords

  • Triple-negative breast cancer
  • Breast cancer stem cells
  • African ancestry
  • Gene expression