Abstract 2549: Activity-regulated cytoskeleton-associated protein (ARC) gene expression is associated with high infiltration of stromal cells and immune cells, but with less cancer cell proliferation and better overall survival in ER-positive/HER2-negative breast cancers
Authors: Yee Gabrielle , Wu Rongrong , Ishikawa Takashi , Takabe Kazuaki 
Published: March 2024

Abstract
Introduction: Recently peritumoral lidocaine infiltration prior to removal was reported to be associated with better survival in early-stage breast cancer (BC). This led us to hypothesize that innervation to the tumor affects its biology and patient survival. Activity-regulated cytoskeleton-associated protein (ARC) gene expression is known to be regulated by neuronal activity. Therefore, we studied the clinical relevance of ARC gene expression as a surrogate of neuronal activity in BC. Methods: Sweden Cancerome Analysis Network-Breast (SCAN-B (GSE96058), n=3273) cohort was analyzed, and the results were validated using The Cancer Genome Atlas (TCGA, n=1069). Results: ER+/HER2- and Luminal A type cancers expressed significantly higher ARC compared to the other subtypes in both cohorts (p&lt;0.005). In the tumor microenvironment, the stromal cells (fibroblasts, endothelial cells and adipocytes) were all found to be significantly infiltrated in high ARC BC (p&lt;0.01). Multiple immune cells were significantly infiltrated in high ARC BC, including CD8, CD4 memory cells, helper type II T cells, regulatory T cells, M1 and M2 macrophages, dendritic cells and B cells (all p&lt;0.03 in both cohorts). In terms of cancer characteristics, there was no difference in silent or nonsilent mutations, single nucleotide variant or indel neoantigens between tumors with low or high ARC expression. However, high ARC BC was significantly associated with less homologous recombination deficiency, intratumor heterogeneity and fraction altered mutation rate compared to low ARC BC in TCGA (p&lt;0.001). High ARC expression was significantly associated with smaller tumor size (p&lt;0.001) and without lymph node metastasis in the SCAN-B cohort (p&lt;0.02), and less Stage IV disease in the TCGA cohort (p&lt;0.02); however, these results were not validated by the other. High ARC BC was significantly associated with lower Nottingham histologic grade and lower MKi67 expression in both cohorts (p&lt;0.001). Cell proliferation-related gene sets in the Hallmark collection (E2F targets, G2M checkpoint, and MTORC1 signaling) were significantly less enriched to high ARC BC consistently in both cohorts. Overall survival (OS) was significantly better in high ARC BC in the ER+/HER2- subtype consistently in both cohorts (p&lt;0.01) and when including all subtypes in the SCAN-B cohort (p&lt;0.001); however this was not validated in TCGA. No significant difference in OS was found between low and high ARC gene expression in triple negative BC in either cohort. Conclusion: ARC gene expression as a surrogate of neuronal activity in BC was associated with high infiltration of stromal cells and immune cells but with less cancer cell proliferation and better overall survival, particularly in the ER+/HER2- subtype.
Citation Format: Gabrielle Yee, Rongrong Wu, Takashi Ishikawa, Kazuaki Takabe. Activity-regulated cytoskeleton-associated protein (ARC) gene expression is associated with high infiltration of stromal cells and immune cells, but with less cancer cell proliferation and better overall survival in ER-positive/HER2-negative breast cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2549.