Abstract PD7-02: Estrogen receptor β suppresses metastasis of inflammatory breast cancer by regulating signaling that promotes cytoskeleton remodeling

Inflammatory breast cancer (IBC) is the most lethal form of breast cancer that accounts for about 10% of breast cancer mortality annually in US. Poor prognosis is largely due to the high propensity of IBC tumors to develop distant metastasis. Owing to the complex metastatic process, the molecular basis of IBC aggressiveness is poorly understood and no specific therapeutic target has been identified. Among the few signaling pathways that differ between IBC and non-IBC is the Rho GTPase that is hyperactivated in many IBC tumors and is associated with cell motility in IBC cells. However, Rho GTPases are not druggable factors and the pathways that activate these proteins in IBC are not fully defined. Another difference is that up to 83% of IBC tumors lack estrogen receptor α (ERα) expression compared with other forms of breast cancer that are mostly ERα-positive. Despite the lack of ERα in the majority of IBC tumors, estrogen may still play a role in these cancers through pathways that involve ERβ. Our tissue staining reveals expression of ERβ in a significant number of IBCs that is reproduced in IBC cell lines. Furthermore, analysis of IBC datasets indicates correlation of receptor expression with good prognosis. We studied this association in preclinical models of IBC by knocking out ERβ in IBC cells. This promotes migration and invasion through cytoskeleton remodeling whereas re-expression of the receptor in knockout cells restores the cytoskeletal structure and migration to the levels of control cells. Consistent with increased migration, deletion of ERβ activates large gene networks of cell de-differentiation including cell surface receptor signaling that enhances Rho GTPase activity to promote the motile phenotype of IBC cells. In contrast, ligands that activate ERβ inhibit the same signaling that contributes to metastasis in IBC. Analysis of orthotopic xenograft models shows that IBC tumors lacking ERβ have higher propensity for metastasis compared with the ERβ-proficient tumors. Conversely, ERβ agonists decrease the metastatic potential of IBC tumors supporting the anti-metastatic activity of the receptor. Our findings point towards a role of ERβ in preventing distant metastases by inhibiting dissemination of IBC cells. This function combined with distinct expression indicates the potential of ERβ to represent a unique prognostic marker and therapeutic target that can be utilized to repress IBC metastasis and eliminate its associated mortality. Citation Format: Christoforos Thomas, Ilias Karagounis, Ratnesh Srivastava, Sushil Kumar, Noelle Francois, Fotis Nikolos, Igor Bado, Hann-Hsiang Chao, Constantinos Koumenis, Savitri Krishnamurthy, Naoto T Ueno, Rumela Chakrabarti, Amit Maity. Estrogen receptor β suppresses metastasis of inflammatory breast cancer by regulating signaling that promotes cytoskeleton remodeling [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD7-02.