Stromal heterogeneity may explain increased incidence of metaplastic breast cancer in women of African descent

Brijesh Kumar, Aditi S. Khatpe, Jiang Guanglong, Katie Batic, Poornima Bhat-Nakshatri, Maggie M. Granatir, Rebekah Joann Addison, Megan Szymanski, Lee Ann Baldridge, Constance J. Temm, George Sandusky, Sandra K. Althouse, Michele L. Cote, Kathy D. Miller, Anna Maria Storniolo and Harikrishna Nakshatri ()
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Brijesh Kumar: Indiana University School of Medicine
Aditi S. Khatpe: Indiana University School of Medicine
Jiang Guanglong: Indiana University School of Medicine
Katie Batic: Indiana University School of Medicine
Poornima Bhat-Nakshatri: Indiana University School of Medicine
Maggie M. Granatir: Indiana University School of Medicine
Rebekah Joann Addison: Indiana University School of Medicine
Megan Szymanski: Indiana University School of Medicine
Lee Ann Baldridge: Indiana University School of Medicine
Constance J. Temm: Indiana University School of Medicine
George Sandusky: Indiana University School of Medicine
Sandra K. Althouse: Indiana University School of Medicine
Michele L. Cote: Richard M. Fairbanks School of Public Health, Indiana University
Kathy D. Miller: Indiana University School of Medicine
Anna Maria Storniolo: Indiana University School of Medicine
Harikrishna Nakshatri: Indiana University School of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-22

Abstract: Abstract The biologic basis of genetic ancestry-dependent variability in disease incidence and outcome is just beginning to be explored. We recently reported enrichment of a population of ZEB1-expressing cells located adjacent to ductal epithelial cells in normal breasts of women of African ancestry compared to those of European ancestry. In this study, we demonstrate that these cells have properties of fibroadipogenic/mesenchymal stromal cells that express PROCR and PDGFRα and transdifferentiate into adipogenic and osteogenic lineages. PROCR + /ZEB1 + /PDGFRα+ (PZP) cells are enriched in normal breast tissues of women of African compared to European ancestry. PZP: epithelial cell communication results in luminal epithelial cells acquiring basal cell characteristics and IL-6-dependent increase in STAT3 phosphorylation. Furthermore, level of phospho-STAT3 is higher in normal and cancerous breast tissues of women of African ancestry. PZP cells transformed with HRasG12V ± SV40-T/t antigens generate metaplastic carcinoma suggesting that these cells are one of the cells-of-origin of metaplastic breast cancers.

Date: 2023
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DOI: 10.1038/s41467-023-41473-6

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