The Influence of Adipogenic Progenitors and Duffy-Null Phenotype on the Normal Breast and Breast Cancer Biology of Women of African Descent
Abstract
This Expansion Award will continue to further characterize the unique biology behind aggressive breast cancers in African-American (AA) women. Triple-negative breast cancers (TNBCs) with poor outcome are more common among AA women compared to women of European ancestry. Even when AA women develop the less aggressive luminal A breast cancer, outcomes tend to be worse compared to women of European ancestry. While socioeconomic factors and disparities in healthcare access are a few of the contributing factors, ancestry-dependent genetic differences in the normal breast biology as contributing factors are just beginning to be recognized. This latest development is in large part due to the availability of genomic information of individuals with different ethnicities and genetic backgrounds. For example, a breast cancer susceptibility variant locus affecting the expression of a microRNA called miR-3065 is enriched in AA women. Individuals in sub-Saharan Africa carry an inactivating mutation in a gene called atypical cytokine receptor 1 (ACKR1 or DARC). This phenotype is called the duffy-null phenotype. The duffy-null phenotype confers protection against malarial infection. However, breast cancer patients with the duffy-null phenotype have worse outcomes compared to AA women with the duffy wild-type phenotype. We analyzed DNA from 100 AA women and found that 7% of them are duffy-null and 32% are duffy-heterozygous (one mutant and one wild-type). Thus, the breast cancer biology in ~40% of AA women is likely different from that in other 60% of AA women, which has not been taken into consideration in the clinic. We also found that the normal breast tissue of AA women is enriched for unique cells called PZP cells. PZP cells, under appropriate conditions, can convert into epithelial cells from which tumors originate or can become fat cells, bone cells, or fibroblasts, which can enhance the growth of tumors. PZP cells likely require the activity of a protein called PDGFRa. Interestingly, PZP cells are important in breast cancer development as their numbers increased only in the cancer-containing breasts of women of European ancestry. Clinical translation of the above knowledge requires establishment of model systems to experimentally evaluate the importance of PZP cells and duffy-null/heterozygous epithelial cells in breast cancer. This was achieved in the last funding period. We have created PZP cell lines from five AA women, which gained the epithelial phenotype upon transformation with oncogenes. We have created breast epithelial cell lines from duffy-null/heterozygous AA women. These cells compared to duffy wild-type cells showed elevated levels of a signaling molecule called c-MET. c-MET makes cancer grow fast and resist treatments. Inhibitors such as crizotinib are currently in the clinic as a treatment for a specific subtype of small cell lung cancer. From these results, we hypothesize that PZP cells and the duffy-null phenotype confer distinct biology to the normal and cancerous breast tissue in AA women. Understanding this biology would enable streamlining of treatments, such as developing c-MET and PDGFRa inhibitors against breast cancers in a subgroup of AA women. Experiments described in two aims will test the above hypothesis. The first aim will focus on PZP cells. We will convert PZP cells into epithelial cells, fibroblasts, bone cells, or fat cells and examine how these converted cells influence the growth of admixed tumor cells. The ability of PZP-derived epithelial cells themselves to become cancerous will be examined. We will determine whether clinically used nilotinib (PDGFRa inhibitor) can reduce the activity of PZP cells and sensitize breast cancers to chemotherapy. The second aim will focus on duffy-null/heterozygous cells. Duffy-null/heterozygous and duffy wild-type cells from AA women will be converted into cancer cells using defined oncogenes and differences in growth and metastas
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010577
Entities
People
- Harikrishna Nakshatri
Organizations
- Indiana University
- United States Army