Endocrine Abstracts

Objective: Estrogen receptors α and β are members of the nuclear receptor family which regulate target gene expression in response to estrogens and to growth factor receptors-mediated pathways. CXCR4 is a chemokine receptor whose physiological ligand is the stromal-derived-factor-1 (SDF-1), a chemokine with proliferative and chemotactic functions. Recently, we reported that ERβ activity can be modulated by the tyrosine kinase ErbB2/ErbB3 receptors and also by the CXCR4 receptor. We sought to determine the crosstalk between ErbB2, CXCR4 and the transcriptional regulation of ERβ.

Methods: The interplay between CXCR4 and ErbB2 receptors was analyzed by co-immunoprecipitation and Western analyses, as well as the signaling pathways involved. The effect on ERβ transcriptional activity was determined by luciferase reporter assay.

Results: Our results indicate that ERβ transcriptional activity was repressed by ErbB2 activation, an effect which was relieved by CXCR4. However, addition of CXCR4 ligand SDF-1 did restore the reduction in ERβ activity, suggesting a ligand-dependent effect of CXCR4. Under these conditions, Akt kinase activity was diminished in presence of CXCR4 and increased with SDF-1 treatment. We also found that CXCR4 altered PI3-K recruitment to ErbB2/ErbB3 receptor dimer, resulting in a decreased interaction between ERβ and Akt in response to ErbB2 when CXCR4 was expressed. Interestingly, these interactions were restored back in presence of SDF-1.

Conclusion: These results indicate a regulatory crosstalk that impacts ERβ transcriptional activity through the ErbB2 signaling pathway modulated by the presence of CXCR4 and its ligand SDF-1, and suggest that it is a PI3-K/Akt dependent process.

Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.

Funding: This work was supported however funding details unavailable.