Research Projects

Female breast cancer accounted for 24.5% of all cancer cases and 15.5% of cancer deaths worldwide, ranking first for incidence and mortality [1, 2]. Notably, breast cancer in Indian women accounts for 25-32%, including 31% incidence of triple-negative breast cancer (TNBC) [3]. Tumor heterogeneity, cancer stem cells, metastasis and drug resistance have a serious clinical consequence for breast cancer patients. Despite promising preclinical data, most of the targeted therapies failed in early clinical trials. The root causes of clinical trial failures are lack of knowledge in cell-of-origin, inter-individual variability in pliancy of breast epithelial cells, cancer-specific genomic instability in genesis of specific molecular subtypes, metastatic patterns and targeted therapies of breast cancer. As per American Cancer Society latest estimate (2011-2021) breast cancer mortality rate in women of African American ancestry (AA) is significantly higher compared with European Americans (EA) women, despite lower incidence of breast cancer in AA. Hispanic/Latino Americans (HA) women have lower cancer incidence, less aggressive and 4-years longer life expectancy [4, 5]. The incidence of young-onset and the most aggressive TNBC is significantly higher in Indian and AA than EA and HA suggesting that the biology of normal breast epithelial cells between these ethnic groups differ, which may contribute to altered susceptibility to tumor initiation, progression and/or metastasis. We and other groups with the normal breasts of women of AA, EA and HA ancestry showed the variability in stem/basal, luminal progenitor, mature/differentiated, multi-potent stem cells, and organogenesis-enriched epithelial/mesenchymal hybrid cells [6-8]. AA women display the enrichment of CD44high/CD24- cells, multi-potent stem cells, stemness features and EMT genes, while higher levels of differentiated cells are enriched in HA women [9]. Remarkably, a unique cell population called PZP (PROCR+/ZEB1+/PDGFRα+) cells discovered within the normal breasts of AA women that could be the cause of increased incidence of TNBC [6, 9]. Additionally, we found differences in pliancy of breast epithelial cells with the same genetic alterations, tumor initiation, progression and/or metastasis between women of AA, EA and HA ancestry [10]. Therefore, the tumor heterogeneity could be a product of interaction between cell-of-origin and driver mutations. Our overarching goal is to elucidate whether normal breast epithelial population in Indian women determines the phenotype of breast cancer in this ethnic group. This proposal will primarily address the challenge “why some breast cancers become life-threatening through metastasis” in Indian population with an emphasis on ethnicity-dependent differences in the intrinsic property of normal breast epithelial cells as one of the contributing factors in metastasis. The cell lines developed in this study will be useful for targeted-drug discovery and screening.