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

Authors

• 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

Publication/Presentation Date

4-17-2018

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

Volume

115

Issue

16

First Page

3673

Last Page

3673

ISSN

1091-6490

Published In/Presented At

Zhao, L., Huang, S., Mei, S., Yang, Z., Xu, L., Zhou, N., Yang, Q., Shen, Q., Wang, W., Le, X., Lau, W. B., Lau, B., Wang, X., Yi, T., Zhao, X., Wei, Y., Warner, M., Gustafsson, J. Å., & Zhou, S. (2018). Pharmacological activation of estrogen receptor beta augments innate immunity to suppress cancer metastasis. Proceedings of the National Academy of Sciences of the United States of America, 115(16), E3673–E3681. https://doi.org/10.1073/pnas.1803291115

Disciplines

Business Administration, Management, and Operations | Health and Medical Administration | Management Sciences and Quantitative Methods

PubMedID

29592953

Department(s)

Administration and Leadership

Document Type

Article