The Influence of Adipogenic Progenitors and Duffy-Null Phenotype on the Normal Breast and Breast Cancer Biology of Women of African Descent
Abstract
Breast cancers in women of African ancestry tend to be highly aggressive and metastatic compared to breast cancers in women of European ancestry. Among women of African descent, breast cancers in those who are duffy-heterozygous or duffy-null genotype are even more aggressive. In the year1 report, as part of aim 1, we showed increased number of a stromal cell type called PZP (PROCRplus/ZEB1plusPDGFRalphaplus) cells in healthy breast tissues of women of African ancestry compared to European or Latina ancestry. PZP cells display fibroadipogenic and mesenchymal stem-like properties. In this report we show that PZP cells can be differentiated into adipocytes or osteocytes under appropriate growth conditions. In co-culture conditions, PZP: epithelial cell communication resulted in luminal epithelial cells acquiring basal/stem cell characteristics and increased expression of IL-6 suggesting the impact of this communication on the microenvironment and breast epithelial hierarchy. Consistent with this possibility, the level of phospho-STAT3, which is a downstream target of IL-6, was higher in the normal and cancerous breast tissues of women of African ancestry compared to women of European ancestry. PZP cells transformed with HRasG12V SV40-T/t antigens generated metaplastic carcinoma in NSG mice suggesting that these cells could be the cell-of-origin of metaplastic breast cancers. Incidence of metaplastic carcinoma is higher in women of African ancestry compared to women of European ancestry. Collectively, these results identify a stromal cell component that could influence the biology of breast cancer in AA women. When PZP cells are implanted along with transformed breast epithelial cells, they localize like stroma in a tumor. These observations now allow us to determine whether their presence decrease sensitivity of tumors to chemotherapy. For aim 2, we generated transformed cell lines from a donor who is duffy heterozygous and two from duffy-null.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2022
- Accession Number
- AD1192313
Entities
People
- Harikrishna Nakshatri
Organizations
- Indiana University Bloomington