Role of hormones in mammary cancer initiation and progression

Breast cancer, the most frequent spontaneous malignancy diagnosed in women in the Western world, is a classical model of hormone dependent malignancy. There is substantial evidence that breast cancer risk is associated with prolonged exposure to female hormones, since early onset of menarche, late menopause, hormone replacement therapy and postmenopausal obesity are associated with greater cancer incidence. Among these hormonal influences a leading role is attributed to estrogens, either of ovarian or extra-ovarian origin, as supported by the observations that breast cancer does not develop in the absence of ovaries, ovariectomy causes regression of established malignancies, and in experimental animal models estrogens can induce mammary cancer. Estrogens induce in rodents a low incidence of mammary tumors after a long latency period, and only in the presence of an intact pituitary axis, with induction of pituitary hyperplasia or adenomas and hyperprolactinemia. Chemicals, radiation, viruses and genomic alterations have all been demonstrated to have a greater tumorigenic potential in rodents. Chemical carcinogens are used to generate the most widely studied rat models; in these models hormones act as promoters or inhibitors of the neoplastic process. The incidence and type of tumors elicited, however, are strongly influenced by host factors. The tumorigenic response is maximal when the carcinogen is administered to young and virgin intact animals in 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 stimulus. Administration of carcinogen to pregnant, parous or hormonally treated virgin rats, on the other hand, fails to elicit a tumorigenic response, 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 dependent are manifested during the postmenopausal period. Estradiol plays a crucial role in their development and evolution. However, it is still unclear whether estrogens are carcinogenic to the human breast. The apparent carcinogenicity of estrogens is attributed to receptor-mediated stimulation of cellular proliferation. Increased proliferation could result in turn in accumulation of genetic damage and stimulation of the synthesis of growth factors that act on the mammary epithelial cells via an autocrine or paracrine loop. Alternatively estrogens may induce cell proliferation through negative feedback by removing the effect of one or several inhibitory factors present in the serum. Multidisciplinary studies are required for the elucidation of the mechanisms responsible for the initiation of breast cancer. Understanding of such mechanisms is indispensable for developing a rational basis for its prevention and control.