Abstract B013: Understanding the anti-metastatic activity of estrogen receptor β in inflammatory breast cancer

Abstract

Abstract Inflammatory breast cancer (IBC) is a highly metastatic breast carcinoma with high frequency of estrogen receptor a (ERα) negativity. We previously explored the second ER subtype, (ERβ) and reported expression in IBC tissues and correlation with reduced metastasis in patients. We have also seen decreased metastasis of IBC tumors in vivo when ERβ was expressed or activated by agonists. Mechanistically, we found that ablation of ERβ in IBC cells increased actin-based cell migration and activated gene expression that promote Rho GTP signaling and cytoskeleton reorganization. Because migratory cells undergo metabolic and epigenetic adaptations that enable them to evade immune surveillance and progress to metastasis, we have now followed an integrated approach to fully understand the role of ERβ as a driver of interconnected transcriptional programs that function to inhibit aggressive phenotypes. We have mapped ERβ binding sites in IBC cells and interrogated this information with gene expression data to identify downstream targets that prevent IBC cells from gaining metastatic traits. Through analysis of cells that express endogenous ERβ and upon its activation by agonists we have defined how a physiologically relevant receptor interacts with the cancer genome to adjust differentiation, metabolism and tumor host interactions to mitigate the metastatic propensity of IBC cells. We compared target genes in normal and malignant tissues and associated their expression with clinical outcomes to strengthen their biological relevance and evaluate their potential use as molecular targets. Our findings thus offer ample opportunities to advance our understanding about endocrine mechanisms that operate within the tumor microenvironment to regulate metastasis with the potential to discover novel targets for therapy intervention. Citation Format: Ilias Karagounis, Spyros Tastsoglou, Harika Nagandla, Naoto Ueno, Amit Maity, Artemis Hatzigeorgiou, Christoforos Thomas. Understanding the anti-metastatic activity of estrogen receptor β in inflammatory breast cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr B013.