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

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 transforming growth factor beta 3 (TGF-β3). Subsequently, CD8 + T lymphocytes recruited to bone metastases escaped TGF-β 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 breast cancer patients. Thus, this study reveals that ERRα regulates immune properties in the bone microenvironment that contributes to decreasing metastatic growth.

FABP4 deactivates NF‐κB‐IL1α pathway by ubiquitinating ATPB in tumor‐associated macrophages and promotes neuroblastoma progression

“…RNA sequencing results revealed multiple cytokines and chemoattractants were upregulated. Considering both CCL1 and CCL20, which screened as the most upregulated chemoattractants, are T cell attracting factors and mainly responsible for Treg cell migration to the TME in human breast and lung cancers, [28][29][30] we identified other eight differential cytokines (IL1A, CXCL3, IL1B, IL23A, CXCL1, CCL2, CXCL8, and IL6) with higher local expressions, and verified by RT-PCR analysis. All of these eight cytokines were upregulated in CMs of FABP4-knockdown macrophages and downregulated in CMs of FABP4-overexpression macrophages (Figure S4D).…”

Bone metastasis: mechanisms, therapies, and biomarkers

“…In addition, these findings demonstrate that CD8 + T cells have the potential to act as regulators of tumor growth in bone. This contention is supported by the observation that transcription factor ERRα in murine 4T1 breast cancer cells inhibits the progression of bone metastases by increasing the recruitment of CD8 + T cells in the bone marrow (28). However, this remains to be established for human cancers where our capacity to identify T cell subsets in bone metastatic foci is limited.…”

Effects of Estrogens on Osteoimmunology: A Role in Bone Metastasis

“…ERRα is also clearly involved in effector T cell activation ( 85 , 86 ). In BCa BMet, ERRα expression restrains TGF-β production by cancer cells, leading to exacerbated cytotoxic features in CD8 + T cells in the bone and efficient BMet control ( 87 ). TGF-β has been associated with an increase in the generation and stability of Tregs ( 88 ).…”