Clinical Relevance of Estrogen Reactivity in the Breast Cancer Microenvironment

Abstract Background: Estrogen signals play an important role in the phenotype of estrogen receptor positive breast cancer (BC). However, comprehensive analyses of the effect of estrogen signals on the tumor microenvironment (TME) and treatment response in large cohorts of primary BC patients have been lacking. We aimed to test the hypothesis that estrogen reactivity effects gene expression and immune cell infiltration profiles in the TME and relates to response to chemotherapy (CT) and endocrine therapy (ET). Methods: A total of 3091 BC cases were analyzed; 1075 from TCGA cohort, 1904 from METABRIC cohort, and 112 from Hokkaido University hospital cohort. We divided the group into estrogen reactivity-high and estrogen reactivity-low groups utilizing estrogen response genes.Results: BC with high estrogen reactivity was related to Myc targets, Metabolism-related signaling, cell stress response, TGF-beta signaling, androgen response, and MTORC1 signaling gene sets in the TME. Low estrogen reactivity was related to immune-related proteins, IL2-STAT5 signaling, IL6-JAK-STAT3 signaling, KRAS signaling, cell cycle related gene sets, and EMT. In addition, BC with high levels of estrogen reactivity had low immune cytolytic activity, low levels of immunostimulatory cells, and high levels of immunosuppressive cells. It also had low levels of stimulatory and inhibitory factors of the cancer immunity cycle (CIC). Patients with high estrogen reactivity were also associated with a better prognosis. Regarding the effect of estrogen reactivity on treatment, patients who were treated with ET and CT but relapsed (BC with CT rec) were related with higher levels of E2F targets and G2M checkpoint, but lower levels of immunosuppressive M2 macrophages or Tregs cells. In addition, the TME in CT rec had higher levels of CIC regulators.Conclusions: We demonstrated the relationship between estrogen reactivity and the profiles of immune cells and gene expression within the TME, as well as the treatment effect of CT given in addition to ET.