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.