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

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

Research output: Contribution to journalArticle

20 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)E3673-E3681
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number16
DOIs
StatePublished - Apr 17 2018

Keywords

  • Cancer metastasis
  • ERβ
  • IL-1β
  • LY500307
  • Neutrophil

ASJC Scopus subject areas

  • General

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