ITIH5 Project

ITIH5 is a novel putative metastasis suppressor gene in breast cancer with a very strong prognostic significance.

ITIH5 was identified already in 2004 by our research group as a new member of the ITI gene family of extracellular matrix proteins (Himmelfarb et al.). ITIH5 shows a significant loss of expression in breast cancer. Due to its supposed biological function as a matrix stabilizer and initial functional experiments, it was suggested that ITIH5 is a putative novel metastasis suppressor gene.

Our research group was the first to describe that ITIH5 is a class II tumor suppressor gene (C2TSG) in human breast cancer (Veeck et al.). In both cell line models and in 170 breast tumors, ITIH5 promoter DNA methylation was identified as the main mechanism of ITIH5 gene inactivation, which was highly significantly (p<0.001) associated with loss of ITIH5 mRNA expression. Furthermore ITIH5 promoter methylation was highly associated with a shortened recurrence-free (p=0.0045) and overall survival (p=0.008) of breast cancer patients. Interestingly, ITIH5 promoter methylation was also strongly associated with both lymph node and long-distance metastases (p=0.003 and p=0.047 respectively), which clearly supports our working hypothesis that ITIH5 is a novel metastasis suppressor gene of breast cancer.

Recently we could decipher in more depth, how ITIH5 is suppressing tumor development and progression on the molecular level (Rose et al.). In mouse model of metastasis, ITIH5 expressing breast cancer cells (MDA-MB-231) almost completely failed to initiate lung metastases. In these metastatic cells ITIH5 modulated cell-matrix adhesion dynamics. The profile of integrin receptors was shifted towards β1-integrin accompanied by decreased Rac1 and increased RhoA activity in ITIH5-expressing clones while cell polarization and single-cell migration was impaired. Instead ITIH5 expression triggered the formation of epithelial-like cell clusters that underwent an epigenetic reprogramming. Thus we show evidence that ITIH5 triggers a reprogramming of breast cancer cells with known stem CSC properties towards an epithelial-like phenotype through global epigenetic changes effecting other known tumor suppressor genes like DAPK1.

In another recent publication (Rose et al.), we provided evidence that ITIH5 may represent a novel modulator of TGF-β superfamily signaling involved in suppressing breast cancer metastasis. By performing in vitro stimulation of TGF-β signaling using TGF-β1 and BMP-2 we showed that ITIH5 triggered downregulation of TGF-β superfamily targets like Id1, known to endorse metastasis.