Estrogen Receptor β-Mediated Inhibition of Actin-Based Cell Migration Suppresses Metastasis of Inflammatory Breast
Christoforos Thomas1, Ilias V Karagounis2, Ratnesh K Srivastava3
1Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. thomaschristoforos@gmail.com Amit.Maity@uphs.upenn.edu.
Abstract:
Inflammatory breast cancer (IBC) is a highly metastatic breast carcinoma with high frequency of estrogen receptor α (ERα) negativity. Here we explored the role of the second ER subtype, ERβ, and report expression in IBC tumors and its correlation with reduced metastasis. Ablation of ERβ in IBC cells promoted cell migration and activated gene networks that control actin reorganization, including G-protein-coupled receptors and downstream effectors that activate Rho GTPases. Analysis of preclinical mouse models of IBC revealed decreased metastasis of IBC tumors when ERβ was expressed or activated by chemical agonists. Our findings support a tumor-suppressive role of ERβ by demonstrating the ability of the receptor to inhibit dissemination of IBC cells and prevent metastasis. On the basis of these findings, we propose ERβ as a potentially novel biomarker and therapeutic target that can inhibit IBC metastasis and reduce its associated mortality. SIGNIFICANCE: These findings demonstrate the capacity of ERβ to elicit antimetastatic effects in highly aggressive inflammatory breast cancer and propose ERβ and the identified associated genes as potential therapeutic targets in this disease.
Insights
Estrogen receptor beta (ERβ) inhibits metastasis in aggressive inflammatory breast cancer (IBC). Targeting ERβ may offer new therapeutic strategies to reduce IBC spread and mortality.
Area of Science:
- Oncology
- Molecular Biology
- Endocrinology
Background:
- Inflammatory breast cancer (IBC) is an aggressive carcinoma often negative for estrogen receptor alpha (ERα).
- The role of the other estrogen receptor subtype, ERβ, in IBC metastasis is not well understood.
Purpose of the Study:
- To investigate the expression and function of ERβ in inflammatory breast cancer.
- To determine if ERβ can inhibit IBC cell migration and metastasis.
Main Methods:
- Analysis of ERβ expression in IBC tumors.
- In vitro studies of IBC cell migration upon ERβ ablation.
- Activation of gene networks controlling actin reorganization and Rho GTPases.
- Preclinical mouse models of IBC to assess metastasis with ERβ expression or activation.
Main Results:
- ERβ expression was observed in IBC tumors and correlated with reduced metastasis.
- Ablation of ERβ increased IBC cell migration and activated specific gene networks.
- ERβ activation by chemical agonists decreased metastasis in preclinical IBC models.
Conclusions:
- ERβ exhibits a tumor-suppressive role in inflammatory breast cancer by inhibiting cell dissemination.
- ERβ represents a potential novel biomarker and therapeutic target for reducing IBC metastasis and mortality.
- Identified ERβ-associated genes may also serve as therapeutic targets in IBC.
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