Estrogen Receptor Beta Shown to Act as Tumor Suppressor in Patients with Inflammatory Breast Cancer

Estrogen receptor beta (ERβ) was shown to act as a mediator of estrogen signaling and a tumor suppressor in inflammatory breast cancer (IBC), according to the results of a study published in Oncotarget.

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The prospect of anti-metastatic activity of ERβ was investigated by researchers using high throughput gene expression and functional analysis of IBC cells with different ERβ levels.

Through micro-array analysis, the investigators found genes that were associated with actin-based cell migration enriched in ERβ knockout KPL4 cells. This was confirmed by increased immunofluorescent staining for polymerized actin.

A Rho GTPase assay found that, consistent with the formation of actin stress fibers, there was a substantial increase in active forms of the cytoskeleton remodeler RhoC upon ERβ knockout, and a significant decrease following treatment of ERβ proficient cells with the agonist LY500307, the investigators wrote.

This finding led to the suggestion by the researchers that RhoC was an essential driver of the migratory phenotype of IBC cells in absence of ERβ due to RhoC’s previous implication in the migration of IBC cells and its depletion, which reversed the increased invasion of ERβ knockout IBC cells.

Next, the authors turned to the pathway of G protein-coupled receptors (GPCR) that are known to activate Rho GTPases through guanine nucleotide exchange factors (GEF) which then catalyze exchange of GDP to GTP. Specifically, they focused on the GEF-interacting protein ELMO1 that is required for the function of GEFs and GPCR GPR141, which could help them identify ERβ-associated regulators of RhoC.

The relevance of these genes was confirmed by the observations that their mRNA and protein levels were selectively upregulated in IBC cell lines and their expression was found to be inversely proportional to ERβ in IBC cell models. Their knockdown significantly reduced the invasive potential of ERβ knockout cells, the researchers found.

A further discovery showed that the protein levels of active RhoC, ELMO1, and phosphorylated Akt were very diminished in ERβ knockout IBC cells upon depletion of GPR141, which clearly established the function of ELMO1 and RhoC downstream of GPR141 in the pathway that regulates migration in IBC cells, the investigators wrote.

Investigators conducted a genomic analysis that revealed the presence of estrogen response elements in the regulatory regions of GPR141 and ELMO1 genes, from which they found a strong binding of ERβ to the promotors of GPR141 and ELMO1. This demonstrated the direct regulation of GPR141 and ELMO1 by ERβ in IBC cells.

The investigators said the study shed new light onto the biology of IBC metastasis by discovering new roles for estrogen signaling in disease progression and identifying new responsive genes that could function as drivers for aggressive phenotypes.

The tumor suppressive nature of ERβ had been previously documented in other diverse cancer types such as kidney and prostate cancer. A prior study from the same research group was the first to examine ERβ levels in clinical specimens of patients with IBC.

“The discovery of new associated factors prompts additional research to evaluate their power as complementary biomarkers in prognosis and molecular targets that may lead to new treatments to overcome resistance and prolong survival in patients. But most of all, this work represents a timely manifestation of the major function of ERβ in cancer,” the study investigators concluded.

Reference

Nagandla H and Thomas C. ERβ as a mediator of estrogen signaling in inflammatory breast cancer. Oncotarget. 2023;576-578(14). doi:10.18632/oncotarget.28425