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.: Abstract*). 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.: Abstract*). 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.: Abstract*). 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.: Abstract*), 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.