Association of triple negative breast cancer (TNBC) with high thermogenesis with worse survival and unfavorable tumor microenvironment (TME).
Authors: Shipra Gandhi, Masanori Oshi, Elizabeth A. Repasky, Kazuaki Takabe
Journal: Journal of Clinical Oncology (2021)

e12546 Background: Norepinephrine released during cold stress by housing 4T1 TNBC mice at 22°C increases tumor growth with a pro-tumorigenic TME [lower CD8 + T-cells, higher myeloid derived suppressor cells (MDSC) and regulatory T-cells (Treg)] compared with mice housed at 30°C. Norepinephrine activates thermogenesis in adipose tissue. Worse survival has been reported among females with malignancies living in cold versus warm climate. These findings led us to hypothesize that TNBC with enhanced thermogenesis is associated with worse outcome and unfavorable TME. Methods: mRNA expression data for 298 and 143 TNBC patients was accessed from METABRIC and GSE96058 breast cancer cohorts, respectively. TNBC were classified into “high” (top tertile) and “low” thermogenesis (bottom two-third) using Gene Set Variation Analysis (GSVA) with KEGG thermogenesis pathway. Computer algorithms xCell and Gene Set Enrichment Analysis (GSEA) were used. Interferon (IFN)-γ signature was calculated using GSVA. Gene expression data was used to quantify adipocytes, angiogenesis, chemokines and cytolytic activity (CYT). R software was used for analysis. False discovery rate (FDR) &lt; 0.25 for GSEA and p &lt; 0.05 was considered statistically significant. Results: High-thermogenesis TNBC was associated with a worse median disease specific survival 14.7 years vs. not reached [HR 1.49 (95% CI 1.02-2.18)], p &lt; 0.05 in METABRIC and a trend towards worse overall survival in both METABRIC and GSE96058. Higher fraction of adipocytes (p &lt; 0.001) and angiogenesis markers including CD31, vWF, Vascular endothelial cadherin, claudin 5, JAM2 and sphingosine-1-phosphate related gene S1PR1 (p &lt; 0.01) were observed explaining the worse survival in high-thermogenesis TNBC. This group was significantly enriched in fatty acid metabolism and adipogenesis pathways (FDR &lt; 0.25) on GSEA. On the other hand, low-thermogenesis TNBC was enriched in mitotic spindle, E2F targets, G2M checkpoint, MYC targets consistent with higher Ki67 (p &lt; 0.05) in this group; and also in IFN-α and IFN-γ response (FDR &lt; 0.25). High-thermogenesis TNBC was associated with lower IFN-γ and granzyme B expression (p &lt; 0.05). Favorable cytotoxic-T cell attracting chemokines CCL5, CXCL9, CXCL10 and CXCL11 were lower; MDSC-, Treg-favoring chemokine CXCL12 was higher (p &lt; 0.05). There were lower M1 and more M2 macrophages (p &lt; 0.001) with lower CYT. There was higher expression of dual-specificity phosphatase-1 ( DUSP1)(p &lt; 0.05), which is upregulated following glucocorticoid receptor activation. Conclusions: We investigated the clinical relevance of preclinical findings and observed that high-thermogenesis TNBC is associated with worse survival and unfavorable TME. Further research is warranted to validate if high thermogenesis could reflect tumors under thermal stress and develop novel strategies to abrogate stress and improve outcomes.