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(American Journal of Pathology. 2004;164:1627-1633.)
© 2004 American Society for Investigative Pathology

Clostridium perfringens Enterotoxin Elicits Rapid and Specific Cytolysis of Breast Carcinoma Cells Mediated through Tight Junction Proteins Claudin 3 and 4

Scott L. Kominsky*, Mustafa Vali*, Dorian Korz*, Theodore G. Gabig{dagger}, Sigmund A. Weitzman{ddagger}, Pedram Argani§ and Saraswati Sukumar*

From the Breast Cancer Program, Sidney Kimmel Comprehensive Cancer Center* and the Department of Pathology,§ Johns Hopkins University School of Medicine, Baltimore, Maryland; the Biomedical Research Institute,{dagger} North Shore-Long Island Jewish Health System, Manhasset, New York; and Northwestern University Medical School,{ddagger} Chicago, Illinois

Clostridium perfringens enterotoxin (CPE) induces cytolysis very rapidly through binding to its receptors, the tight junction proteins CLDN 3 and 4. In this study, we investigated CLDN 3 and 4 expression in breast cancer and tested the potential of CPE-mediated therapy. CLDN 3 and 4 proteins were detected in all primary breast carcinomas tested (n = 21) and, compared to normal mammary epithelium, were overexpressed in approximately 62% and 26%, respectively. Treatment of breast cancer cell lines in culture with CPE resulted in rapid and dose-dependent cytolysis exclusively in cells that expressed CLDN 3 and 4. Intratumoral CPE treatment of xenografts of T47D breast cancer cells in immunodeficient mice resulted in a significant reduction in tumor volume (P = 0.007), with accompanying necrosis. Necrotic reactions were also seen in three freshly resected primary breast carcinoma samples treated with CPE for 12 hours, while isolated primary breast carcinoma cells underwent rapid and complete cytolysis within 1 hour. Thus, expression of CLDN 3 and 4 sensitizes primary breast carcinomas to CPE-mediated cytolysis and emphasizes the potential of CPE in breast cancer therapy.




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