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

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

  • Proc Natl Acad Sci U S A. 2018 Apr 17;115(16):E3673-E3681. doi: 10.1073/pnas.1803291115.
Linjie Zhao 1,  Shuang Huang 1,  Shenglin Mei 2,  Zhengnan Yang 1,  Lian Xu 3,  Nianxin Zhou 1,  Qilian Yang 1,  Qiuhong Shen 1,  Wei Wang 4,  Xiaobing Le 1,  Wayne Bond Lau 5,  Bonnie Lau 6,  Xin Wang 4,  Tao Yi 1,  Xia Zhao 1,  Yuquan Wei 1,  Margaret Warner 7 8,  Jan-Åke Gustafsson 9 8,  Shengtao Zhou 10
Affiliations

Affiliations

  • 1 Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children of Ministry of Education and State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University and Collaborative Innovation Center, 610041 Chengdu, People's Republic of China.
  • 2 Shanghai Key Laboratory of Tuberculosis, Clinical Translational Research Center, Shanghai Pulmonary Hospital, Tongji University, 200433 Shanghai, People's Republic of China.
  • 3 Department of Pathology, West China Second Hospital of Sichuan University, 610041 Chengdu, People's Republic of China.
  • 4 Department of Biomedical Sciences, City University of Hong Kong, 999077 Kowloon Tong, Hong Kong, People's Republic of China.
  • 5 Department of Emergency Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107.
  • 6 Department of Surgery, Emergency Medicine, Kaiser Permanente Santa Clara Medical Center (affiliate of Stanford University), Santa Clara, CA 95051.
  • 7 Department of Biology and Biochemistry, Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, TX 77204.
  • 8 Department of Biosciences and Nutrition, Novum, Karolinska Institute, 14186 Stockholm, Sweden.
  • 9 Department of Biology and Biochemistry, Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, TX 77204; jgustafs@central.uh.edu taotaovip2005@163.com.
  • 10 Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children of Ministry of Education and State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University and Collaborative Innovation Center, 610041 Chengdu, People's Republic of China; jgustafs@central.uh.edu taotaovip2005@163.com.
PMID: 29592953 DOI: 10.1073/pnas.1803291115
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.

Keywords

ERβ; IL-1β; LY500307; cancer metastasis; neutrophil.

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