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Objectives: Uterine serous papillary carcinoma (USPC) represents a highly aggressive variant of endometrial cancer characterized by early lymphatic and intra-abdominal spreading and an inborn resistance to chemotherapy. The discovery of novel and effective therapy against advanced or recurrent USPC remains a high priority. Methods: Using expression profiling we have recently reported claudin-3 and claudin-4 genes to be highly expressed in USPC. Because these tight junction proteins represent the low and high affinity receptors, respectively, for the cytotoxic Clostridium Perfringens Enterotoxin (CPE), and are sufficient to mediate CPE binding and trigger subsequent toxin-mediated cytolysis within few minutes, in this study we investigated the potential use of CPE as a novel therapy against chemotherapy resistant USPC. Results: We report that 100% (13 out of 13) of the primary flash frozen USPC tested overexpress one or both CPE-receptors by quantitative RT-PCR. Both cytoplasmic and membranous staining for claudin-4 protein expression was noted in the majority of USPC specimens (i.e., 90% score 3+ and 2+ by immunohistochemistry). In contrast, only low levels of membranous staining for claudin-4 protein was found in normal endometrial control (NEC) tissue samples. When primary USPC cell lines were incubated with different concentrations of CPE in vitro a dose-dependent cytotoxic effect was demonstrated. Importantly, all four primary chemotherapy resistant USPC cell lines available to this study were found to express claudin-3 and claudin-4 genes at high levels and, regardless of their resistance to chemotherapeutic agents, died within 1 hr to the exposure to 3.3 μg/mL of CPE in vitro. Conclusions: Our results highlight novel molecular features of USPC and provide a foundation for the development of new type-specific therapies against this highly aggressive variant of endometrial cancer.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]