THE ETIOPATHOGENESIS OF BREAST-CANCER PREVENTION

Breast cancer, the most frequent malignancy diagnosed in women, continues to increase in incidence in all industrialized nations. The fact that this disease becomes incurable once it has spread to regional or distant sites indicates that its complexity is beyond our present level of knowledge. A better understanding of the etiopathogenesis and biology of breast cancer is required in order to develop a rational basis for its prevention and therapy. The observation that early parity reduces the risk of developing breast cancer indicates that reproductive and hormonal conditions might play an important role in its prevention. The elucidation of the mechanisms mediating this protection requires the availability of adequate experimental models. The induction of rat mammary carcinomas with chemical carcinogens has proven to be useful for these purposes, especially since, in this model, full-term pregnancy or treatment of virgin rats with a placental hormone, human chorionic gonadotropin (hCG), prior to the administration of the carcinogen protects the mammary gland from tumor development. Since both pregnancy and hCG treatment induce differentiation of the mammary gland, this process is considered to be essential for the inhibition of the neoplastic process. The possibility of preventing breast cancer by treating young nulliparous females with hormones that mimic a full term pregnancy is of practical interest to the human female population, but it requires a thorough knowledge of the development of the human breast. Our studies indicate that the breast of postpubertal nulliparous women is composed of lobular structures reflecting different stages of development. Type I lobules are the most undifferentiated. Type 2 lobules evolve from the previous ones; they are composed of a higher number of ductular structures per lobule. They progress to lobules types 3 and 4, which are present in the breast during pregnancy and lactation. The type 1 lobule, considered to be the site of origin of ductal carcinomas, predominates in the breast of nulliparous women of all ages. In parous women, the type 3 lobule is the most frequent. Primary cultures derived from breast tissues composed of type 1 lobules express phenotypes of cell transformation not observed in cells derived from type 3 lobules. These data acquire relevance in the light that women with a history of early pregnancy are at a lower risk of developing breast cancer than nulliparous women, an effect attributed to differences in the degree of differentiation of the breast. Pregnancy furthers the differentiation of type 1 lobules to type 3, making them refractory to neoplastic transformation. These data provide useful intermediate endpoints for evaluating new strategies developed for breast cancer prevention.