Hormonal approach to breast cancer prevention.

Abstract

Breast cancer is more frequent in nulliparous women, while its incidence is significantly reduced by full-term pregnancy. The fact that the protection conferred by pregnancy is observed in women from different countries and ethnic groups, regardless of the endogenous incidence of this malignancy, indicates that this protection does not result from extrinsic factors specific to a particular environmental, genetic, or socioeconomic setting, but rather from an intrinsic effect of parity on the biology of the breast. Using an experimental system we have shown that treatment of young virgin rats with human chorionic gonadotropin (hCG), like full-term pregnancy, efficiently inhibits the initiation and progression of chemically induced mammary carcinomas. Treatment of young virgin rats with hCG induced a profuse lobular development of the mammary gland, reduced the proliferative activity of the mammary epithelium, and induced the synthesis of inhibin, a secreted protein with tumor-suppressor activity. HCG treatment also increased the expression of the programmed cell death (PCD) genes testosterone repressed prostate message 2 (TRPM2), interleukin 1-beta-converting enzyme (ICE), p53, c-myc, and bcl-XS, induced apoptosis, and downregulated cyclins. PCD genes were activated through a p53-dependent process, modulated by c-myc, and with partial dependence on the bcl-2 family-related genes. The possibility that this hormonal treatment activates known or new genes was tested by differential display technique. We have identified a series of new genes, hormone-induced-1 (HI-1) among them. The characterization of their functional role will contribute to clarify the mechanisms through which hCG inhibits the initiation and progression of mammary cancer. Of great significance was the observation that PCD genes remained activated even after lobular formations had regressed due to the cessation of hormone administration. We postulate that this mechanism plays a major role in the long-lasting protection exerted by hCG from chemically induced carcinogenesis, and might be also involved in the lifetime reduction in breast cancer risk induced in women by full-term pregnancy. The implications of these observations are two-fold: on one hand, they indicate that hCG, as pregnancy, may induce early genomic changes that control the progression of the differentiation pathway, and on the other, that these changes are permanently imprinted in the genome, regulating the long-lasting refractoriness to carcinogenesis. The permanence of these changes, in turn, makes them ideal surrogate markers of hCG effect in the evaluation of this hormone as a breast cancer preventive agent.