Primary prevention of breast cancer by hormone-induced differentiation.

Breast cancer is a fatal disease whose incidence is gradually increasing in most industrialized countries and in all ethnic groups. Primary prevention is the ultimate goal for the control of this disease. The knowledge that breast cancer risk is reduced by early full-term pregnancy and that additional pregnancies increase the rate of protection has provided novel tools for designing cancer prevention strategies. The protective effect of pregnancy has been experimentally reproduced in virgin rats by treatment with the placental hormone human chorionic gonadotropin (hCG). HCG prevents the initiation and inhibits the progression of chemically induced mammary carcinomas by inducing differentiation of the mammary gland, inhibiting cell proliferation, and increasing apoptosis. It also induces the synthesis of inhibin, a tumor suppressor factor, downregulates the level of expression of the estrogen receptor alpha (ER-alpha) by methylation of CpG islands, imprinting a permanent genomic signature that characterizes the refractory condition of the mammary gland to undergo malignant transformation. The genomic signature induced by hCG is identical to that induced by pregnancy and is specific for this hormone. Comparison of the mammary gland's genomic profile of virgin Sprague-Dawley rats treated daily with hCG for 21 days with that of rats receiving 17beta-estradiol (E2) and progesterone (Pg) (E2 + Pg) revealed that in hCG-treated rats 194 genes were significantly up-modulated (> 2.5 log2-folds) (p < 0.01) and commonly expressed, whereas these genes were not expressed in the E2 + Pg group. The genomic signature induced by hCG and pregnancy included activators or repressors of transcription genes, apoptosis, growth factors, cell division control, DNA repair, tumor suppressor, and cell-surface antigen genes. Our data indicate that hCG, like pregnancy, induces permanent genomic changes that are not reproduced by steroid hormones and in addition regulates gene expression through epigenetic mechanisms that are differentiation-dependent processes, leading us to conclude that hormonally induced differentiation offers enormous promise for the primary prevention of breast cancer.