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

Sep 24, 2026

Uploaded by Adam

Research addresses how genetic ancestry may drive differences in breast cancer incidence and outcomes. Prior work identified ZEB1-expressing cells near ductal epithelium enriched in women of African ancestry. This study shows these cells behave like fibroadipogenic/mesenchymal stromal cells, express PROCR and PDGFRα, transdifferentiate into adipogenic and osteogenic lineages, and that PZP cells promote luminal cells acquiring basal traits via IL-6/STAT3 signaling. Phospho-STAT3 levels are higher across normal and cancer tissues in African ancestry.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages22

Reading Time55 min

AccessFree to download

Background

Stromal cell characterization and lineage potential

PZP cells and epithelial communication

IL-6/STAT3 signaling and phospho-STAT3 differences

Clinical disparities and rationale for study

Linking ancestry, socioeconomic stress, and tumor biology

Article [https://doi.org/10.1038/s41467-023-41473-6](https://doi.org/10.1038/s41467-023-41473-6) Stromal heterogeneity may explain increased incidence of metaplastic breast cancer in women of African descent Received: 13 July 2022 | Accepted: 5 September 2023 | | --- | | | | Check for updates | Brijesh Kumar1,8,9, Aditi S. Khatpe1,2,9, Jiang Guanglong 3, Katie Batic1, Poornima Bhat-Nakshatri1, Maggie M. Granatir4, Rebekah Joann Addison4, Megan Szymanski4, Lee Ann Baldridge4, Constance J. Temm4, George Sandusky 4, Sandra K. Althouse5, Michele L. Cote6, Kathy D. Miller3, Anna Maria Storniolo 3 & Harikrishna Nakshatri 1,2,7 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 PROCRand 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 oneofthe cellsof-origin of metaplastic breast cancers. Population-based research consistently reports that African American women have the highest incidence and mortality rates from triple negative breast cancer (TNBC) compared other racial and ethnic groups despite adjustment for socioeconomic and other contributing factors1. Even in cases of estrogen receptor positive (ER+)/HER2-/node negative breast cancers with intermediate Oncotype recurrence scores2, clinical outcome is worse in African American women compared to non-Hispanic White women3. Furthermore, ductal carcinoma in situ (DCIS), which is typically considered to be of minimal risk of recurrence, tends to be more deleterious to African American women compared to non-Hispanic White women4. Additionally, disparities in pathologic complete response among patients receiving neoadjuvant therapy has been reported, with lower response rates in Black women5. These studies have all relied on self-reported race and ethnicity, which are not biologically-deﬁned, but are instead social constructs that have changed over time6. Martini et al. went beyond these classiﬁcations and utilized biological markers associated with country of origin and reported distinct immunologic landscapes within TNBC tumors from 1Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA. 2Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA. 3Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA. 4Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA. 5Department of Biostatistics and Health Data Science, Indiana University School of Medicine, Indianapolis, IN 46202, USA. 6Richard M. Fairbanks School of Public Health, Indiana University, Indianapolis, IN 46202, USA. 7VA Roudebush Medical Center, Indianapolis, IN 46202, USA. 8Present address: School of Biomedical Engineering, Indian Institute of Technology (Banaras Hindu University), Varanasi, UP 221005, India. 9These authors contributed equally: Brijesh Kumar, Aditi S. Khatpe. e-mail: [hnakshat@iupui.edu](hnakshat@iupui.edu) women of African ancestry (AA) compared to women of European ances

FAQs

What cells are investigated as a potential ancestry-related contributor in normal breast tissue?

The study focuses on ZEB1-expressing cells adjacent to ductal epithelial cells, enriched in women of African ancestry in prior work and characterized further here as PROCR+/ZEB1+/PDGFRα+ (PZP) cells.

What biological properties do the PROCR+/ZEB1+/PDGFRα+ (PZP) cells show?

PZP cells express PROCR and PDGFRα and can transdifferentiate into adipogenic and osteogenic lineages, resembling fibroadipogenic/mesenchymal stromal cells.

How does IL-6/STAT3 signaling relate to epithelial changes described in the study?

The study reports that PZP-mediated epithelial cell communication leads to luminal epithelial cells acquiring basal cell characteristics, accompanied by an IL-6-dependent increase in STAT3 phosphorylation.

Sep 24, 2026

Uploaded by Adam