Enhanced Thermogenesis in Triple-Negative Breast Cancer Is Associated with Pro-Tumor Immune Microenvironment.

Shipra Gandhi,Vijayashree Murthy,Masanori Oshi,Kazuaki Takabe,Elizabeth A Repasky

doi:10.3390/cancers13112559

Abstract

Simple SummaryPreclinical studies have shown that cold stress results in the activation of thermogenesis and an increased tumor growth rate in mice. This study aimed to investigate the clinical relevance of these laboratory findings in patients with triple-negative breast cancer using publicly available large cohorts. Triple-negative breast cancers with high thermogenesis were found to have a pro-tumorigenic immune microenvironment, which may explain the trend towards poor survival observed in this group. This study investigated thermogenesis as a biomarker to predict clinical outcomes, and may pave the way to test novel therapeutics to improve the outcomes of this breast cancer subtype.Mild cold stress induced by housing mice with a 4T1 triple-negative breast cancer (TNBC) cell implantation model at 22 °C increases tumor growth rate with a pro-tumorigenic immune microenvironment (lower CD8 +T cells, higher myeloid-derived suppressor cells (MDSCs) and regulatory T-cells (Tregs)). Since cold stress also activates thermogenesis, we hypothesized that enhanced thermogenesis is associated with more aggressive cancer biology and unfavorable tumor microenvironment (TME) in TNBC patients. A total of 6479 breast cancer patients from METABRIC, TCGA, GSE96058, GSE20194, and GSE25066 cohorts were analyzed using Kyoto Encyclopedia of Genes and Genomes (KEGG) thermogenesis score. High-thermogenesis TNBC was associated with a trend towards worse survival and with angiogenesis, adipogenesis, and fatty acid metabolism pathways. On the other hand, low-thermogenesis TNBC enriched most of the hallmark cell-proliferation-related gene sets (i.e., mitotic spindle, E2F targets, G2M checkpoint, MYC targets), as well as immune-related gene sets (i.e., IFN-α and IFN-γ response). Favorable cytotoxic T-cell-attracting chemokines CCL5, CXCL9, CXCL10, and CXCL11 were lower; while the MDSC- and Treg-attracting chemokine CXCL12 was higher. There were higher M2 but lower M1 macrophages and Tregs. In conclusion, high-thermogenesis TNBC is associated with pro-tumor immune microenvironment and may serve as biomarker for testing strategies to overcome this immunosuppression.

Highlights

Thermogenesis is essential for all animals, ensuring a stable temperature for cellular and physiological functions under conditions of environmental challenge
Given that the preclinical 4T1 murine triple-negative breast cancer (TNBC) cell-line implanted model shows increased tumor growth rate and metastasis during cold stress [8], and because of the literature showing that cold stress results in activation of the thermogenesis pathway [4], we hypothesized that human TNBC with enhanced thermogenesis is associated with increased tumor growth and with poor survival
We examined this in three independent TNBC cohorts: METABRIC (n = 298), TCGA (n = 153), and GSE96058 (n = 141)

Summary

Introduction

Thermogenesis is essential for all animals, ensuring a stable temperature for cellular and physiological functions under conditions of environmental challenge. The energy released from muscle contractions produces heat, while brown adipocytes mainly produce heat in non-shivering thermogenesis. The sympathetic nervous system primarily controls thermogenesis in brown and beige adipose tissue by releasing norepinephrine in response to cold stimuli. Brown adipocytes express uncoupling protein 1 (UCP1). The association between complex V and the electron transport chain (ETC) is uncoupled by UCP1, a mitochondrial carrier protein, resulting in dissipation of the proton gradient across the inner mitochondrial membrane. Via this uncoupling, heat is generated instead of ATP [3]. Sympathetic denervation of the adipose tissue inhibits the cold-induced UCP1 expression [4]

Objectives

Methods

Results