Claudins As markers for Early Detection, Diagnosis, Prognosis and as Targets of Therapy for breast Cancer

We have recently identified Claudins 1, 3, 4, and 7 as differentially expressed in breast cancer relative to normal breast tissue. Further studies have shown Claudins 1 and 7 to be down-regulated in primary breast cancers relative to normal breast epithelium. We have generated a rabbit anti-peptide polyclonal antibody, specific for Claudin-7 in both Western and immunohistochemical analysis. Using this antibody in immunohistochemistry we have found that the down-regulation of Claudin-7 occurs predominantly in grade III ductal carcinoma in situ (DCIS) and grade III invasive breast cancer (IBC), suggesting that Claudin-7 may serve as a useful prognostic marker for breast cancer (1). Studies to determine the value of Claudin-1, 3 and 4 in this regard are currently being conducted. While Claudins 1 and 7 appear to be under-expressed in breast cancer, we have found Claudins-3 and 4 to be expressed at equal or higher levels in primary breast cancers relative to normal breast epithelium. Using a commercially available antibody we have developed an ELISA based test for the detection of Claudin-3 and 4 expressing cells in both ductal lavage fluid and blood. Detection of Claudin-3 or 4 in ductal lavage fluid may allow the early detection of breast cancer, while detection of Claudin-3 or 4 in blood may provide evidence for metastasis.Claudins 3 and 4 function as receptors for Clostridium perfringens enterotoxin (CPE). Binding of CPE to these claudins results in efficient and specific cell lysis. Since we have found Claudins 3 and 4 to be expressed on breast cancer cells we have tested the potential use of CPE in breast cancer therapy. Our studies have shown that CPE treatment of both human and rodent breast cancer cell lines in vitro results in efficient cell lysis. Further, treatment of human breast cancer xenografts in SCID mice with CPE results in tumor cell death corresponding with a reduction in tumor volume. We are currently testing this therapy in animal models using intraductal injection, which functions to limit systemic toxicity and thereby increase therapeutic efficacy. Preliminary studies show that intraductal administration of CPE to rodent breast tumors results in tumor cell death concordant with a reduction in tumor volume. In addition, no systemic toxicity was observed. Description (Set) Proposed Use (Set) Claudins 1 and 7 could potentially be used in prognostic applications. Claudins 3 and 4 could be used in diagnostic applications for breast cancer as well as breast cancer metastasis. CPE could be used as a therapy for breast cancer as well as to prevent invasive breast cancer by destroying precancerous lesions through intraductal administration

Inventor(s): Sukumar, Saraswati V.

Type of Offer: Licensing



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