Chorionic gonadotropin inhibits rat mammary carcinogenesis through activation of programmed cell death

Human chorionic gonadotropin (hCG) inhibits the progression of 7,12-dimethylbenz[a]anthracene (DMBA) induced mammary carcinomas. In order todetermine whether this phenomenon was mediated by induction of programmedcell death or apoptosis, 45-day-old virgin Sprague-Dawley rats received 8mg DMBA/100 g body weight; 20 days later they were injected daily with 100IU hCG for 40 days (DMBA + hCG group). Age- matched untreated, hCG- andDMBA + saline treated rats were used as controls. Tissues were collected atthe time of DMBA administration and at 5, 10, 20 and 40 days of hCGinjection. RNA from mammary glands, adenocarcinomas and ovaries was probedfor transforming growth factors (TGF) alpha and beta, and the apoptoticgenes TRPM2, ICE, bcl2, bcl-XL, bcl-XS, p53 and c-myc. The mammary glandsof hCG-treated animals with or without DMBA exhibited elevated expressionof TRPM2, ICE, bcl-XS, c- myc and p53; and elevation in the apoptoticindex. Mammary adenocarcinomas developed in those animals treated with hCGshowed an elevation in the expression of p53, c-myc and ICE genes incomparison with the levels detected in the adenocarcinomas developed by theanimals treated with DMBA alone. No significant alterations in theexpression of any of the genes tested was observed in ovarian RNAs. Theseresults led us to conclude that hCG induces programmed cell death in themammary gland initiated in the carcinogenic process, that this process isp53 dependent, and is modulated by c-myc expression. Our data also indicatethe possibility that a cell death program dependent on the bcl2 familyexists, because of the potential involvement of p53, bcl-XS and Bax inapoptosis. This additional mechanism of tumor inhibition makes hCGtreatment a useful approach for the prevention and therapy of breastcancer.