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

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

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...

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Bibliographic Details
Published in:Nature communications Vol. 14; no. 1; pp. 5683 - 22
Main Authors: Kumar, Brijesh, Khatpe, Aditi S., Guanglong, Jiang, Batic, Katie, Bhat-Nakshatri, Poornima, Granatir, Maggie M., Addison, Rebekah Joann, Szymanski, Megan, Baldridge, Lee Ann, Temm, Constance J., Sandusky, George, Althouse, Sandra K., Cote, Michele L., Miller, Kathy D., Storniolo, Anna Maria, Nakshatri, Harikrishna
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 14-09-2023
Nature Publishing Group
Nature Portfolio
Subjects:
13/105
13/106
13/109
13/21
13/31
13/95
38/88
42/44
631/67/327
631/67/68
631/67/70
64/60
692/4028/67/1347
692/420
82/1
82/51
96/1
96/106
96/109
96/21
96/31
96/44
Antigens
Breast cancer
Carcinoma
Cell interactions
Enrichment
Epithelial cells
Epithelium
Heterogeneity
Humanities and Social Sciences
multidisciplinary
Phosphorylation
Science
Science (multidisciplinary)
Stat3 protein
Stromal cells
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Summary: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. P ROCR + / Z EB1 + / P DGFRα+ (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 HRas G12V  ± SV40-T/t antigens generate metaplastic carcinoma suggesting that these cells are one of the cells-of-origin of metaplastic breast cancers. Breast cancer patients of African ancestry face worse clinical outcomes, so understanding related cellular and molecular features remains critical. Here, the authors show that stromal cells that are particularly enriched in breast cancer patients with African ancestry can trans-differentiate into different lineages and can be transformed into metaplastic carcinoma.
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ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-023-41473-6