Abstract 1507: Investigation of estrogen receptor-modulated association between immune activities and patient survival in breast cancer
Authors: Chang Yi-Hsuan , Chiu Yu-Chiao , Lu Tzu-Pin , Lai Liang-Chuan , Tsai Mong-Hsun , Hsiao Tzu-Hung , Chuang Eric Y 
Published: July 2016

In breast cancer, estrogen receptor (ER) is a crucial biomarker for subtyping and predicting patients’ prognosis. Nonetheless, its modulation of immune-related genes and survival was rarely discussed. Addressing this, in the present study we devised a comprehensive analysis to compare the survival associations of immune genes between ER+ and ER- breast tumors. Specifically, we modeled immune activities by a gene set enrichment analysis of 31 immunologic gene sets defined by a recent study. Whole-genome expression profiles and ER status of 279 breast cancer patients (245 ER+ and 34 ER-) were downloaded from the Gene Expression Omnibus (GSE4922); another dataset was incorporated for validation (GSE2034).

Nine immunologic gene sets were significantly predictive of relapse-free survival (RFS) in a ER+ specific manner (Cox P-values&lt;0.05 in ER+ and &gt;0.05 in ER-). In order to investigate the modulation of ER in gene set interactions, we calculated the Pearson correlation coefficients between gene sets in ER+ and ER- cohorts, respectively. The gene sets formed two coexpression clusters in ER+ patients (all correlation coefficients&gt;0.7); one cluster was composed of protective gene sets (with hazard ratios &lt;1) of dendritic cells, T cell regulatory, eosinophil, and mast cell, and the other included risk gene sets of CD4, CD8, and effector memory CD4. Interestingly, no significant intra-cluster correlation appeared in the ER- condition. We also identified inter-cluster inverse correlation between mast cell and CD8 or effector memory CD4 in ER+ patients (correlation coefficients&lt;-0.6). We reason that one of the clusters accounts for naïve immune system and the other represents adaptive immune system, and crosstalk between the two systems is facilitated by inter-cluster interactions. Using an independent dataset of breast tumors (GSE2034), we corroborated all the identified intra- and inter-cluster correlated pairs (correlation coefficients&gt;0.6 and &lt;-0.45 for intra- and inter-cluster pairs, respectively). To further dissect the functional relevance of these ER-modulated immune activities, we performed Gene Set Enrichment Analysis (GSEA) to identify differentially activated biological functions between patients with high and low enrichment scores of an immunologic gene set. GSEA revealed significant associations with breast cancer grades, subtypes, and metastasis.

In conclusion, using a gene set framework we comprehensively investigated the involvement of ER in modulating between immune activities and prognosis. Further biological investigations into our findings are warranted.

Citation Format: Yi-Hsuan Chang, Yu-Chiao Chiu, Tzu-Pin Lu, Liang-Chuan Lai, Mong-Hsun Tsai, Tzu-Hung Hsiao, Eric Y Chuang. Investigation of estrogen receptor-modulated association between immune activities and patient survival in breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1507.