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 year3, we completed all proposed studies of aim 1 and published results in Nature Communications. We showed increased number of a stromal cell type called PZP (PROCR+/ZEB1+PDGFRalpha+) 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. These cells can be differentiated into adipocytes or osteocytes under appropriate growth conditions. Inco-culture conditions, PZP:epithelial cell communication resulted in luminal epithelial cells acquiring basal/stem cell characteristics and increased expression ofIL-6 suggesting the impact of this communication on the microenvironment and breast epithelial hierarchy. Based on these results, through independent funding resource, a multi-institutional clinical trial will be initiated. NCT05846789 will investigate whether adding the IL-6R inhibitor tocilizumab to carboplatin improves response in women with triple negative breast cancer. Importantly, this trial will enroll separate cohorts of Black and non-Hispanic White women, supporting critical cross-race comparisons. For aim 2, we had difficulty in establishing immortalized cell lines from duffy-null carriers, which has now been resolved. We were able to generate immortalized cell lines from duffy null carriers using a combination of hTERT+SV40-T/t antigens. Two cell lines from duffy-null and one from duffy-heterozygous carriers have been created. Compared to cells from women of African ancestry with duffy-wild type alleles, duffy mutation carrier cells contain higher levels of pAKT suggesting elevated growth factor/PI3K signaling activity.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2023
- Accession Number
- AD1217500
Entities
People
- Harikrishna Nakshatri
Organizations
- Indiana University Bloomington