Project Summary The aggressiveness of triple negative breast cancers (TNBCs) is, in part, due to their metastatic behavior, propensity to recur rapidly and dismal low response to standard-of-care chemotherapies. TNBCs are associated with the worst prognosis and clinical outcomes, especially in African American (AA) women. Interestingly, the incidence rate of TNBC is more than 2-fold higher in AA women, compared with their Caucasian American (CA) counterparts who have the same disease. These racial-associated disparities in outcomes, that remain poorly understood, are significant even after controlling for socioeconomic and treatment variations, and suggest the contribution of differences in tumor biology to these disparities in cancer outcomes. We identified YB1, a multifunctional gene, as a potential biological driver of TNBC disparities in AA women. We also found that the oncogenic signaling of YB1 may play a major role in activating the invasion-metastasis cascade and therapy resistance of TNBC in AA women. YB1 expression levels are significantly higher in AA tumors and are strongly associated with poorer overall survival in AA TNBC patients. YB1 nuclear localization/phosphorylation (S102) is also correlated with cancer stem cell phenotype, and resistance to chemotherapy in TNBC tumors of AA origin. Based on this strong evidence, we developed the overarching hypothesis that YB1 oncogenic signaling is a major contributing factor to differences in disease outcomes between AA and CA TNBC patients. This hypothesis will be addressed by investigating the biologic and clinical significance of YB1 signaling axis in TNBC disparities. Our proposal will also attempt to better elucidate the complex interactions between genetics, environment, socioeconomics and lifestyle that may contribute to the observed differences with the ultimate goal of developing and implementing more efficacious population-based strategies to improve health equity for this vulnerable population. Our specific aims will (1) Determine the impact of YB1 signaling (expression, phosphorylation and nuclear localization) in tumorigenicity and chemoresistance in TNBC cell lines and tumors of AA origin; (2) Determine the impact of novel combination therapies targeting YB1 to alleviate progression and metastasis of AA TNBC tumors; and (3) Determine whether YB1 signaling can predict racial disparities and chemoresistance in TNBC, based on transcriptomics and immunohistochemistry. We are very confident that our innovative proposal will make great contributions to the field of cancer disparities, especially for AA women with TNBC, and will identify new YB1-based therapeutic options for this devastating cancer that is disparately affecting AA women.

Project Narrative / Public Health Relevance Triple negative breast cancer (TNBC) is a highly lethal form of breast cancer, that disparately affects African American (AA) compared with Caucasian American (CA) women with more than 2-fold increase in death rate in AA, even after adjusting for socioeconomic position, age at diagnosis, and treatment modalities. Recently, we discovered that this disparity may be the result of increased oncogenic activity of the YB1 gene signaling and its associated signaling pathways, which contribute to therapy resistance and the aggressiveness of TNBC tumors in AA women. Our innovative proposal has the potential to lead to new YB1-targeted treatment options, predict those patients who would benefit from these targeted approaches, and provide a biomarker for progression and therapy resistance of TNBC in AA women.