ERRα Expression in Bone Metastases Leads to an Exacerbated Antitumor Immune Response

Cancer Res. 2020 Jul 1;80(13):2914-2926. doi: 10.1158/0008-5472.CAN-19-3584. Epub 2020 May 4.

Abstract

Bone is the most common metastatic site for breast cancer. Although the estrogen-related receptor alpha (ERRα) has been implicated in breast cancer cell dissemination to the bone from the primary tumor, its role after tumor cell anchorage in the bone microenvironment remains elusive. Here, we reveal that ERRα inhibits the progression of bone metastases of breast cancer cells by increasing the immune activity of the bone microenvironment. Overexpression of ERRα in breast cancer bone metastases induced expression of chemokines CCL17 and CCL20 and repressed production of TGFβ3. Subsequently, CD8+ T lymphocytes recruited to bone metastases escaped TGFβ signaling control and were endowed with exacerbated cytotoxic features, resulting in significant reduction in metastases. The clinical relevance of our findings in mice was confirmed in over 240 patients with breast cancer. Thus, this study reveals that ERRα regulates immune properties in the bone microenvironment that contributes to decreasing metastatic growth. SIGNIFICANCE: This study places ERRα at the interplay between the immune response and bone metastases of breast cancer, highlighting a potential target for intervention in advanced disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism*
  • Bone Neoplasms / immunology
  • Bone Neoplasms / metabolism
  • Bone Neoplasms / prevention & control*
  • Bone Neoplasms / secondary
  • Breast Neoplasms / immunology
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Breast Neoplasms / prevention & control*
  • Cell Proliferation
  • Chemokine CCL17 / genetics
  • Chemokine CCL17 / metabolism
  • Chemokine CCL20 / genetics
  • Chemokine CCL20 / metabolism
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Prognosis
  • Receptors, Estrogen / genetics
  • Receptors, Estrogen / metabolism*
  • Signal Transduction
  • T-Lymphocytes / immunology*
  • Transforming Growth Factor beta3 / genetics
  • Transforming Growth Factor beta3 / metabolism
  • Tumor Cells, Cultured
  • Tumor Microenvironment / immunology*
  • Xenograft Model Antitumor Assays

Substances

  • Biomarkers, Tumor
  • CCL17 protein, human
  • CCL20 protein, human
  • Chemokine CCL17
  • Chemokine CCL20
  • ERRalpha estrogen-related receptor
  • Receptors, Estrogen
  • TGFB3 protein, human
  • Transforming Growth Factor beta3