ROLE OF HORMONES IN MAMMARY-CANCER INITIATION AND PROGRESSION

Breast cancer, the most frequent spontaneous malignancy diagnosed in w omen in the Western world, is a classical model of hormone dependent m alignancy There is substantial evidence that breast cancer risk is ass ociated with prolonged exposure to female hormones, since early onset of menarche, late menopause, hormone replacement therapy and postmenop ausal obesity are associated with greater cancer incidence. Among thes e hormonal influences a leading role is attributed to estrogens, eithe r of ovarian or extra-ovarian origin, as supported by the observations that breast cancer does not develop in the absence of ovaries, ovarie ctomy causes regression of established malignancies, and in experiment al animal models estrogens can induce mammary cancer. Estrogens induce in rodents a low incidence of mammary tumors after a long latency per iod, and only in the presence of an intact pituitary axis, with induct ion of pituitary hyperplasia or adenomas and hyperprolactinemia. Chemi cals, radiation, viruses and genomic alterations have all been demonst rated to have a greater tumorigenic potential in rodents. Chemical car cinogens are used to generate the most widely studied rat models; in t hese models hormones act as promoters or inhibitors of the neoplastic process. The incidence and type of tumors elicited, however, are stron gly influenced by host factors. The tumorigenic response is maximal wh en the carcinogen is administered to young and virgin intact animals i n which the mammary gland is undifferentiated and highly proliferating . The atrophic mammary gland of hormonally-deprived ovariectomized or hypophysectomized animals does not respond to the carcinogenic stimulu s. Administration of carcinogen to pregnant, parous or hormonally trea ted virgin rats, on the other hand, fails to elicit a tumorigenic resp onse, a phenomenon attributed to the higher degree of differentiation of the mammary gland induced by the hormonal stimulation of pregnancy. In women a majority of breast cancers that are initially hormone depe ndent are manifested during the postmenopausal period. Estradiol plays a crucial role in their development and evolution. However, it is sti ll unclear whether estrogens are carcinogenic to the human breast. The apparent carcinogenicity of estrogens is attributed to receptor-media ted stimulation of cellular proliferation. Increased proliferation cou ld result in turn in accumulation of genetic damage and stimulation of the synthesis of growth factors that act on the mammary epithelial ce lls via an autocrine or paracrine loop. Alternatively estrogens may in duce cell proliferation through negative feedback by removing the effe ct of one or several inhibitory factors present in the serum. Multidis ciplinary studies are required for the elucidation of the mechanisms r esponsible for the initiation of breast cancer. Understanding of such mechanisms is indispensable for developing a rational basis for its pr evention and control.