Investigation of the role of TIR8/SIGIRR, a new upregulated gene in HER2 posaitive breast tumours, and tis association with the immune response

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 overexpression of HER2 in human breast tumors were investigated using an immortalized mammary epithelial cell (HB4a) and its HER2 overexpressing variant (HB4a-C5.2). Global analysis of gene expression identified SIGIRR, a negative modulator of pro-inflammatory signals triggered by IL-1R and TLRs, as an upregulated gene in the C5.2 variant. Given the dual role of inflammation in tumor initiation and progression, we hypothesize that SIGIRR overexpression in breast tumors may fine-tune inflammation and attenuate the antitumoral adaptive response. We validated the correlation between HER2 and SIGIRR by bioinformatic analysis of public microarray and RNAseq data and by real-time PCR of different HER2+ tumors and breast tumor cell lines. Other preliminary data from our group indicate that the knockdown (KD) of SIGIRR expression in tumor cells increases 2 to 3-fold the activation of NFkB pathway and different pro-inflammatory cytokines expression, such as IL6, IL8, TNF and IFNbeta, and the chemokines CSF2 and CSF3. Conditioned medium derived from KD tumor cells increases neutrophil recruitment and skew polarization of macrophages towards a M1 phenotype. In vivo studies are now been conducted to address the role of SIGIRR in breast tumor progression and its association with the immune infiltrate.