AUTHOR=Takeshita Takashi , Tokumaru Yoshihisa , Oshi Masanori , Wu Rongrong , Patel Ankit , Tian Wanqing , Hatanaka Yutaka , Hatanaka Kanako C. , Yan Li , Takabe Kazuaki 

TITLE=Clinical Relevance of Estrogen Reactivity in the Breast Cancer Microenvironment

JOURNAL=Frontiers in Oncology

VOLUME=Volume 12 - 2022

YEAR=2022

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2022.865024

DOI=10.3389/fonc.2022.865024

ISSN=2234-943X

ABSTRACT=Purpose: Estrogen signals play an important role in the phenotype of estrogen receptor positive breast cancer. However, comprehensive analyses of the effect of estrogen signals on the tumor microenvironment and sur-vival in large cohorts of primary breast cancer patients have been lacking. We aimed to test the hypothesis that estrogen reactivity affects gene expression and immune cell infiltration profiles in the tumor microenvi-ronment and survival. 
Methods: A total of 3098 breast cancer cases were analyzed; 1904 from Molecular Taxonomy of Breast Can-cer (METABRIC) cohort, 1082 from the cancer genome atlas (TCGA) cohort, and 112 from Hokkaido Uni-versity Hospital cohort. We divided the group into estrogen reactivity-high and estrogen reactivity-low groups utilizing the scores of ESTROGEN_RESPONSE_EARLY and ESTROGEN_RESPONSE_LATE in Gene Set Variant Analysis.
Results: Breast cancer 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 tumor microenvironment. 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, breast cancer with high levels of estrogen reactivity had low immune cytolytic activity and low levels of immunostimulatory cells. It also had low levels of stimulatory and inhibitory factors of the cancer immunity cycle. Patients with high estrogen reactivity were also associated with a better prognosis. 
Conclusion: We demonstrated the relationship between estrogen reactivity and the profiles of immune cells and gene expression, as well as survival.