Breast cancer (BrCa) disparities are startling and the levels of racial disparity in metastasis and survival remain unacceptable despite advancements in BrCa screening and treatment that have led to a significant decline in BrCa related deaths. This project addresses BrCa disparities with the goal of identifying cellular and molecular characteristics that certain chemokine receptors contribute to the tumor composition, or microenvironment, across different racial groups. Chemokines and their receptors are critical in determining the metastatic destination of tumor cells by supporting tumor angiogenesis and immune cell recruitment. The chemokine receptors CXCR4 and ACKR3 are co-receptors for the chemokine CXCL12, which is critical in BrCa metastasis. CXCR4 is overexpressed in BrCa tumors and ACKR3 in the tumor vasculature. Our preliminary data indicates ACKR3 and CXCR4 are differentially expressed in opposing directions in bulk breast cancer tumor tissues from different racial groups. We also identified ACKR3 and CXCR4 to be differentially expressed in a sub-set of tumor cells, the tumor endothelial cells. The goal of this project is to elucidate the patterns of ACKR3 and CXCR4 expression in distinct tumor cell subsets and how these receptors contribute to altering the tumor?s composition and eventual dissemination in women from different racial groups. We propose two specific aims to accomplish this goal.
Aim 1 : Determine the ACKR3 and CXCR4 signaling pathways in BrCa from samples of different racial groups. Identifying gene regulatory networks that control expression of ACKR3 and CXCR4 in BrCa across different racial groups will indicate the contribution of these receptors to BrCa disparities.
Aim 2. Identify CR expression on a single-cell level in breast tumor cell subsets from racially diverse patient tissue samples. Distinct cell population functions will be modeled, quantitatively analyzed using BrCa human tissues from different race groups, and validated by testing whether factors that enhance ACKR3 and CXCR4 activity can be reversed by blocking receptor-microenvironment interactions. These findings will reveal the cellular and molecular contributions that drive ACKR3 and CXCR4 to alter the tumor landscape in BrCa disparities, including the tumor vasculature in situ and potentially at metastatic sites. Knowing these molecular features will have far-reaching implications for therapeutic development, better clinical trial development, and ultimately alleviate cancer disparities. In addition, it will enable the PI to develop her research program, gather preliminary data to seek mainstream funding and allow her to offer and engage the ethnically diverse student population at San Francisco State University, including 43% under-represented students, in exciting opportunities to conduct cancer biology research and prepare them to face the challenges of combatting cancer disparities.
The focus of this project is on breast cancer disparities, with the goal of identifying cellular and molecular characteristics that contribute to the tumor microenvironment across different racial groups. We hypothesize that the chemokine receptors ACKR3 and CXCR4 significantly contribute to the tumor microenvironment differences that lead to worse clinical outcomes for black women compared to women of other races. The data we generate from these studies will elucidate molecular interactions and regulation dynamics of tumor cell subsets, set the foundation for testing novel therapeutic-target combinations and ultimately lead to improved design of patient clinical trials that address breast cancer disparities.
