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Serum amyloid A predisposes inflammatory tumor microenvironment in triple negative breast cancer

2019; Impact Journals LLC; Volume: 10; Issue: 4 Linguagem: Inglês

10.18632/oncotarget.26566

1949-2553

Rosa Mistica C. Ignacio, Carla Gibbs, Soohyun Kim, Eun-Sook Lee, Samuel E. Adunyah, Deok‐Soo Son,

Wnt/β-catenin signaling in development and cancer

// Rosa Mistica C. Ignacio 1 , Carla R. Gibbs 1 , Soohyun Kim 2 , Eun-Sook Lee 3 , Samuel E. Adunyah 1 and Deok-Soo Son 1 1 Department of Biochemistry, Cancer Biology, Neuroscience and Pharmacology, Meharry Medical College, Nashville, TN, USA 2 Department of Veterinary Sciences, College of Veterinary Medicine, Kon-Kuk University, Seoul, Republic of Korea 3 Department of Pharmaceutical Sciences, College of Pharmacy, Florida A&M University, Tallahassee, FL, USA Correspondence to: Deok-Soo Son, email: dson@mmc.edu 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 ABSTRACT 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.