CHORIONIC-GONADOTROPIN INHIBITS RAT MAMMARY CARCINOGENESIS THROUGH ACTIVATION OF PROGRAMMED CELL-DEATH

Human chorionic gonadotropin (hCG) inhibits the progression of 7,12-di methylbenz[a]anthracene (DMBA) induced mammary carcinomas, In order to determine whether this phenomenon was mediated by induction of progra mmed cell death or apoptosis, 45-day-old virgin Sprague-Dawley rats re ceived 8 mg DMBA/100 g body weight; 20 days later they were injected d aily with 100 IU hCG for 40 days (DMBA + hCG group), Age-matched untre ated, hCG- and DMBA + saline treated rats were used as controls, Tissu es were collected at the time of DMBA administration and at 5, 10, 20 and 40 days of hCG injection, RNA from mammary glands, adenocarcinomas and ovaries was probed for transforming growth factors (TGF) alpha an d beta, and the apoptotic genes TRPM2, ICE, bcl2, bcG-XL, bcl-XS, p53 and c-myc. The mammary glands of hCG-treated animals with or without D MBA exhibited elevated expression of TRPM2, ICE, bcl-XS, c-myc and p53 ; and elevation in the apoptotic index, Mammary adenocarcinomas develo ped in those animals treated crith hCG showed an elevation in the expr ession of p53, c-myc and ICE genes in comparison with the levels detec ted in the adenocarcinomas developed by the animals treated with DMBA alone, No significant alterations in the expression of any of the gene s tested was observed in ovarian RNAs, These results led us to conclud e that hCG induces programmed cell death in the mammary gland initiate d in the carcinogenic process, that this process is p53 dependent, and is modulated by c-myc expression, Our data also indicate the possibil ity that a cell death program dependent on the bc12 family exists, bec ause of the potential involvement of p53, bcl-XS and Bar in apoptosis, This additional mechanism of tumor inhibition makes hCG treatment a u seful approach for the prevention and therapy of breast cancer.