SEMA6D-mediated breast cancer disparity, metastasis, and tumor-immune interaction

Project Summary Breast cancer (BC) is the most commonly diagnosed cancer in women and is also the second leading cause of cancer death in women. BC lethality is primarily caused by metastasis. African American (AA) women display earlier onset of BC than Caucasian American (CA) women, are more likely to be diagnosed with metastatic types of triple-negative breast cancer (TNBC) at the time of presentation, and have a significantly higher mortality rate. Our long-term goal is to identify the biological factors underlying racial disparities in BC outcomes and to develop novel clinical applications to eliminate such disparities. Our bioinformatic analysis revealed that Semaphorin 6D (SEMA6D) expression was dramatically lower in BC tissues than normal breast tissues. Of note, expression of two prominent isoforms of SEMA6D were reduced in AA cancer tissues compared to CA cancer tissues. The low expression level of SEMA6D correlates significantly with poor patient survival. Our analysis of protein expression confirmed that expression of SEMA6D protein is also lower in AA BC tissues than in CA TNBC tissues. Our functional test showed that overexpression of SEMA6D in BC cells dramatically reduced their metastasis in vivo. To better understand the role of SEMA6D in BC, we performed single cell RNA-Sequencing analysis using spontaneous mouse BC tumors. We found that SEMA6D-deficiency led to increased expression of metastatic genes in tumor cells and enhanced accumulation of a group of immunosuppressive cells in the tumor microenvironment. We hypothesize that SEMA6D inhibits BC metastasis via mechanisms involving both tumor- intrinsic signaling and the tumor microenvironment, and that differential expression of SEMA6D is a causative factor for outcome disparities observed between AA and CA patients. In Aim 1, we will determine the mechanism underlying differential expression of SEMA6D by race in BC samples. In Aim 2, we will test the functional significance of differential expression of SEMA6D in regulating metastasis of AA and CA cells. In Aim 3, we will elucidate the mechanism by which SEMA6D suppresses metastasis of AA and CA TNBC cells. Accomplishing this study will provide crucial clues for understanding the biological basis for BC racial disparities and will facilitate development of novel diagnostic/therapeutic approaches to eliminate such disparities.