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

Author:

Zhao Linjie,Huang Shuang,Mei Shenglin,Yang Zhengnan,Xu Lian,Zhou Nianxin,Yang Qilian,Shen Qiuhong,Wang Wei,Le Xiaobing,Lau Wayne Bond,Lau Bonnie,Wang Xin,Yi Tao,Zhao Xia,Wei Yuquan,Warner Margaret,Gustafsson Jan-Åke,Zhou ShengtaoORCID

Abstract

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 IL1B−/− 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.

Funder

National Natural Science Foundation of China

National Key Research and Development Program of China

Sichuan Science-Technology Soft Sciences Project

Yi Yao Foundation

Sichuan University

Robert A. Welch Foundation

Cancerfonden

Center for Innovative Medicine

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

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