Serum amyloid A predisposes inflammatory tumor microenvironment in triple negative breast cancer
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Rosa Mistica C. Ignacio1, Carla R. Gibbs1, Soohyun Kim2, Eun-Sook Lee3, Samuel E. Adunyah1 and Deok-Soo Son1
1Department of Biochemistry, Cancer Biology, Neuroscience and Pharmacology, Meharry Medical College, Nashville, TN, USA
2Department of Veterinary Sciences, College of Veterinary Medicine, Kon-Kuk University, Seoul, Republic of Korea
3Department of Pharmaceutical Sciences, College of Pharmacy, Florida A&M University, Tallahassee, FL, USA
Deok-Soo Son, email: email@example.com
Keywords: serum amyloid A; proinflammatory; tumor microenvironment; triple negative breast cancer; interleukin-1β
Received: November 12, 2018 Accepted: December 29, 2018 Published: January 11, 2019
Acute-phase proteins (APPs) are associated with a variety of disorders such as infection, inflammatory diseases, and cancers. The signature profile of APPs in breast cancer (BC) is poorly understood. Here, we identified serum amyloid A (SAA) for proinflammatory predisposition in BC through the signature profiles of APPs, interleukin (IL) and tumor necrosis factor (TNF) superfamily using publicly available datasets of tumor samples and cell lines. Triple-negative breast cancer (TNBC) subtype highly expressed SAA1/2 compared to HER2, luminal A (LA) and luminal B (LB) subtypes. IL1A, IL1B, IL8/CXCL8, IL32 and IL27RA in IL superfamily and CD70, TNFSF9 and TNFRSF21 in TNF superfamily were highly expressed in TNBC compared to other subtypes. SAA is restrictedly regulated by nuclear factor (NF)-κB and IL-1β, an NF-κB activator highly expressed in TNBC, increased the promoter activity of SAA1 in human TNBC MDA-MB231 cells. Interestingly, two κB-sites contained in SAA1 promoter were involved, and the proximal region (-96/-87) was more critical than the distal site (-288/-279) in regulating IL-1β-induced SAA1. Among the SAA receptors, TLR1 and TLR2 were highly expressed in TNBC. Cu-CPT22, TLR1/2 antagonist, abrogated IL-1β-induced SAA1 promoter activity. In addition, SAA1 induced IL8/CXCL8 promoter activity, which was partially reduced by Cu-CPT22. Notably, SAA1/2, TLR2 and IL8/CXCL8 were associated with a poor overall survival in mesenchymal-like TNBC. Taken together, IL-1-induced SAA via NF-κB-mediated signaling could potentiate an inflammatory burden, leading to cancer progression and high mortality in TNBC patients.
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