Pharmacological activation of estrogen receptor beta augments innate immunity to suppress cancer metastasis

Abstract

<p id="d4607266e454">Cancer metastases have caused the major mortality rate for cancer patients, with limited options of treatment and unsatisfactory therapeutic efficacy. Unlike the tumor-promoting role of estrogen receptor (ER)α, ERβ has shown potent antitumor effects in many cancers. In this study, we showed that the selective ERβ agonist LY500307 could potently suppress lung metastasis of cancer by recruitment of antitumor neutrophils to the metastatic niche. These chemotactic effects of LY500307 for neutrophils were primarily mediated by ERβ activation-induced IL-1β release by the tumor cells. Our study provides the rationale that pharmacological activation of ERβ could augment innate immunity to suppress cancer metastatic colonization to lung, implicating the potential use of selective ERβ agonists for the treatment of cancer patients with metastasis. </p><p class="first" id="d4607266e457">Metastases constitute the greatest causes of deaths from cancer. However, no effective therapeutic options currently exist for cancer patients with metastasis. Estrogen receptor β (ERβ), as a member of the nuclear receptor superfamily, shows potent tumor-suppressive activities in many cancers. To investigate whether modulation of ERβ could serve as a therapeutic strategy for cancer metastasis, we examined whether the selective ERβ agonist LY500307 could suppress lung metastasis of triple-negative breast cancer (TNBC) and melanoma. Mechanistically, while we observed that LY500307 potently induced cell death of cancer cells metastasized to lung in vivo, it does not mediate apoptosis of cancer cells in vitro, indicating that the cell death-inducing effects of LY500307 might be mediated by the tumor microenvironment. Pathological examination combined with flow cytometry assays indicated that LY500307 treatment induced significant infiltration of neutrophils in the metastatic niche. Functional experiments demonstrated that LY500307-treated cancer cells show chemotactic effects for neutrophils and that in vivo neutrophil depletion by Ly6G antibody administration could reverse the effects of LY500307-mediated metastasis suppression. RNA sequencing analysis showed that LY500307 could induce up-regulation of IL-1β in TNBC and melanoma cells, which further triggered antitumor neutrophil chemotaxis. However, the therapeutic effects of LY500307 treatment for suppression of lung metastasis was attenuated in <i>IL1B</i> ^−/− murine models, due to failure to induce antitumor neutrophil infiltration in the metastatic niche. Collectively, our study demonstrated that pharmacological activation of ERβ could augment innate immunity to suppress cancer metastatic colonization to lung, thus providing alternative therapeutic options for cancer patients with metastasis. </p>