SFRP1 is an important negative regulator of the WNT pathway in human breast cancer.

SFRP1 is an important molecule of the WNT pathway. We were one of the first research group to characterize an SFRP1-specific antibody and showed that SFRP1 protein is completely or almost completely lost in more than 80% of all breast carcinomas (Klopocki et al.: Abstract*). In this project we could further show that loss of SFRP1 occurs early in breast cancer development: Tissue of patients with ductal carcinoma in situ (DCIS) already shows similarly high rates of SFRP1 loss as invasive ductal breast carcinoma (IDC).

Our research group was the first to describe that SFRP1 is a class II tumor suppressor gene (C2TSG) in human breast cancer (Veeck et al.: Abstract*). In the course of tumor development, aberrant methylation of cytosine residues often occurs in the promoter region of tumor suppressor genes. This promoter DNA methylation leads to gene being switched off ("silenced”). We found this epigenetic change in the SFRP1 promoter region in 61% of breast cancer patients analyzed (n=130) and we could show that it is responsible for the transcriptional loss of SFRP1. Beyond that, no gene inactivating mutations were found so that aberrant SFRP1 promoter methylation appears to be the fundamental molecular mechanism of SFRP1 gene silencing in breast cancer. Interestingly, SFRP1 promoter methylation was significantly associated with a shortened overall survival of patients (Veeck et al.: Abstract*).

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.

We have developed a minimally invasive blood based biomarker test consisting of a panel of epigenetic biomarkers for the early detection of breast cancer.

The SNiPER panel comprises the promoter methylation biomarkers SPAG6, NKX2-6, ITIH5 and PER1. The test has high sensitivity and specificity and is applicable for a wider patient group compared to the gold standard mammography, which often has insufficient patient compliance and sometimes poor sensitivity. Blood based biomarkers could lead to higher adherence and early detection of breast cancer, which is key to successful treatment and outcomes.

In 2016, the SNiPER panel already won the PerMediCon Award (1st place) of the Personalized Medicine Convention, a trade fair for personalized medicine in Cologne.

Publication: "SNiPER: a novel hypermethylation biomarker panel for liquid biopsy based early breast cancer detection"

Verleihung der PerMediCon Awards 2016

News: Jolein Mijnes ist Gewinnerin des PerMediCon-Awards 2016