Estrogen Receptor β (ESR2) Transcriptome and Chromatin Binding in a Mantle Cell Lymphoma Tumor Model Reveal the Tumor-Suppressing Mechanisms of Estrogens

SIMPLE SUMMARY: Mantle cell lymphoma (MCL) is much more common in males than in females. The reason for this is not clear, but research has indicated that the female sex hormones, estrogens, have a protective effect on MCL development. To study this further, mice were transplanted with MCL cells and treated with an estrogen that selectively activates ESR2, the main nuclear estrogen receptor in lymphoma cells. The activation of ESR2 resulted in reduced MCL tumor growth of MCL tumors that were both sensitive and resistant to a newly developed drug (ibrutinib). The mechanism for this effect was investigated by analyzing gene expression and ESR2 binding to target genes. The results show that the affected genes were enriched in several malignancy-related biological processes, including MCL. Furthermore, the results suggested an interplay between the lymphoma cells and the tumor microenvironment in response to ESR2 activation. Altogether, the results clarify the mechanisms of ESR2-mediated MCL growth impairment by estrogens and provide a possible explanation for the sex difference in incidence. Furthermore, targeting ESR2 may be an option when considering the treatment of MCL. ABSTRACT: Mantle cell lymphoma (MCL) is a non-Hodgkin lymphoma with one of the highest male-to-female incidence ratios. The reason for this is not clear, but epidemiological as well as experimental data have suggested a role for estrogens, particularly acting through estrogen receptor β (ESR2). To study the ESR2 effects on MCL progression, MCL cells sensitive and resistant to the Bruton tyrosine kinase inhibitor ibrutinib were grafted to mice and treated with the ESR2-selective agonist diarylpropionitrile (DPN). The results showed that the DPN treatment of mice grafted with both ibrutinib-sensitive and -resistant MCL tumors resulted in impaired tumor progression. To identify the signaling pathways involved in the impaired tumor progression following ESR2 agonist treatment, the transcriptome and ESR2 binding to target genes were investigated by genome-wide chromatin immunoprecipitation in Granta-519 MCL tumors. DPN-regulated genes were enriched in several biological processes that included cell–cell adhesion, endothelial–mesenchymal transition, nuclear factor-kappaB signaling, vasculogenesis, lymphocyte proliferation, and apoptosis. In addition, downregulation of individual genes, such as SOX11 and MALAT1, that play a role in MCL progression was also observed. Furthermore, the data suggested an interplay between the lymphoma cells and the tumor microenvironment in response to the ESR2 agonist. In conclusion, the results clarify the mechanisms by which estrogens, via ESR2, impair MCL tumor progression and provide a possible explanation for the sex-dependent difference in incidence. Furthermore, targeting ESR2 with a selective agonist may be an additional option when considering the treatment of both ibrutinib-sensitive and -resistant MCL tumors.