Investigation of the role of SIGIRR/TIR8 in breast tumors and its association with the immune response using a transgenic MMTV-neu/SIGIRR-KO animal model

• Grant number: 13/24133-0
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• Start date: April 09, 2014
• End date: April 08, 2015
• Field of knowledge: Biological Sciences - Immunology - Applied Immunology
• Principal Investigator: Anamaria Aranha Camargo
• Grantee: Luís Felipe Ingrassia Campesato
• Supervisor: Cecilia Garlanda
• Host Institution: Laboratório de Biologia Molecular e Genômica. Instituto Ludwig de Pesquisa sobre o Câncer (ILPC). São Paulo , SP, Brazil
• Institution abroad: Fondazione Humanitas per la Ricerca, Italy
• Associated to the scholarship: 11/23214-0 - Role of SIGIRR on the crosstalk between tumor and immune cells, BP.DR

Abstract

The oncogene ErbB2/HER2 is overexpressed in roughly 30% of all breast tumors and is directly associated with rapid disease progression and poor prognosis, although its molecular mechanisms remain to be better understood. Transcriptional changes associated with the overexpression of ErbB2 in human breast tumors were investigated in our group using an immortalized mammary epithelial cell (HB4a) and its HER2 overexpressing variant (HB4a-c5.2). In a global analysis of gene expression we identified SIGIRR, a negative modulator of pro-inflammatory signals triggered by IL-1R and TLRs, as an upregulated gene in the c5.2 variant. We validated this correlation by bioinformatics analysis of public microarray data and by real-time PCR of different ErbB2+ tumors and breast tumor cell lines. Given the dual role of inflammation in tumor initiation and progression, we hypothesize that HER2-dependent SIGIRR upregulation in breast tumors may fine-tune inflammation and attenuate the antitumoral adaptive response. Preliminary data from our group indicate that SIGIRR expression in tumor cells modulates the activation of NFkB pathway and cytokines expression pattern, also regulating neutrophils and monocytes recruitment in vitro. In collaboration with Dr. Garlanda e Dr. Mantovani's research group, we now intend to use two different animal models to further understand the role of SIGIRR during breast tumor progression: an immunocompetent orthotopic isograft mouse model and a MMTV-neu transgenic model of spontaneously arising breast tumors crossed with SIGIRR-Knockout mice. The use of animal models is crucial to better study the complex interaction of tumor cells and its microenvironment, which is composed of a wide range of infiltrated cells, such as leukocytes and stromal cells. In this project we intend to establish an important collaboration with two key and leading researchers in the tumor immunology area, which also lead the most important group in the study of SIGIRR/TIR8, with several high-impact publications on the subject. (AU)