The Impact of Ethnicity-Dependent Differences in Breast Epithelial Hierarchy on Tumor Incidence and Characteristics
Abstract
Ethnicity-dependent differences in the incidence of specific subtypes of breast cancer have been proven clinically. However, mechanistic studies to understand these differences and to develop therapies have been difficult due to the lack of model systems that allow propagation and experimental manipulation of normal cells from different ethnic groups. Two unique resources/techniques have now enabled us to overcome these limitations: Thousands of volunteers of different ethnic groups have donated their normal breast cores to the Komen Normal Tissue Bank (KTB) housed at the Indiana University Simon Cancer Center for the sole purpose of understanding normal breast biology. Methodology adapted in the lab has allowed the culturing of breast epithelial cells from these cores either immediately after collection or after cryopreservation. Three major findings of studies performed with these cells form the backbone of this proposal: (1) Normal breast cells from women of African American ancestry (AA) contain a unique population of cells, which are enriched for the expression of stemness-associated genes. Another type of cells with stemness-enriched characters is also enriched in the normal breast of AA women. Since these populations of cells were detected in every AA woman tested and ethnicity is self-reported but not verified through genomics, it is likely that cells with these phenotypes are dominant in AA women despite possible intermixing of race/ethnicity. (2) There is enormous heterogeneity in the normal breast of healthy women. Thus, we may need to reinterpret results of studies that identified "actionable signaling networks" by comparing gene expression in cancer with "normal" of unrelated individuals. (3) Comparison of normal and tumor from the same individual showed differences in differentiation status between adjacent normal tissue and tumor cells. The current approach of comparing gene expression in bulk tumor and adjacent normal may fail to identify genes that are causally linked to cancer. Phenotypically similar normal and tumor cells on an individual basis may need to be analyzed to identify cancer-specific defects. Based on the above results, we hypothesize that the hierarchy of breast epithelial cells differs between healthy individuals. There are additional differences between AA and CA women. Cells that are enriched in AA intrinsically express higher levels of stem cell-associated genes that confer inherent motile ability and resistance to treatment. Cancers originating from these cells are likely aggressive with poor outcome. In addition, inter-individual differences in the number of these enriched cells among AA women could determine their susceptibility to aggressive subtypes of breast cancer. Experiments described in two aims will validate our hypothesis. In the first aim, unique cells of AA women and cells that are common to AA and CA women will be made cancerous using define set of oncogenes. Resulting cells will be tested for tumorigenicity, metastasis, and sensitivity to different drugs. If our hypothesis is correct, then the cells that are unique to AA women should form highly aggressive tumors that metastasize. Based on the expression pattern of genes in these cells that we already know, the resulting tumors are likely to be triple-negative breast cancers. In the second aim, we will ask whether genes that are expressed at higher levels in the unique population of cells in AA women can serve as biomarkers that can predict cancer incidence. We will analyze healthy normal, matched adjacent normal, and tumor tissues from different ethnic groups. Impact: As treatment for breast cancer moves toward "personalized medicine" and targeted therapies, there will be a shift from the markers that are currently used where the efficacy of the treatment is determined after years based on survival and disease-free progression to more science and tumor analysis being applied at the ti
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510707
Entities
People
- Harikrishna Nakshatri
Organizations
- Indiana University – Purdue University Indianapolis
- United States Army