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Role of Hormones in Mammary Cancer Initiation and Progression

  • Irma H. Russo
  • Jose Russo
Article

Abstract

Breast cancer, the most frequent spontaneousmalignancy diagnosed in women in the Western world, isa classical model of hormone dependent malignancy. Thereis substantial evidence that breast cancer risk is associated with prolonged exposure to femalehormones, since early onset of menarche, late menopause,hormone replacement therapy and postmenopausal obesityare associated with greater cancer incidence. Among these hormonal influences a leading roleis attributed to estrogens, either of ovarian orextra-ovarian origin, as supported by the observationsthat breast cancer does not develop in the absence of ovaries, ovariectomy causes regression ofestablished malignancies, and in experimental animalmodels estrogens can induce mammary cancer. Estrogensinduce in rodents a low incidence of mammary tumors after a long latency period, and only in thepresence of an intact pituitary axis, with induction ofpituitary hyperplasia or adenomas andhyperprolactinemia. Chemicals, radiation, viruses andgenomic alterations have all been demonstrated to have a greatertumorigenic potential in rodents. Chemical carcinogensare used to generate the most widely studied rat models;in these models hormones act as promoters or inhibitors of the neoplastic process. Theincidence and type of tumors elicited, however, arestrongly influenced by host factors. The tumorigenicresponse is maximal when the carcinogen is administered to young and virgin intact animals in which themammary gland is undifferentiated and highlyproliferating. The atrophic mammary gland ofhormonally-deprived ovariectomized or hypophysectomizedanimals does not respond to the carcinogenic stimulus.Administration of carcinogen to pregnant, parous orhormonally treated virgin rats, on the other hand, failsto elicit a tumorigenic response, a phenomenon attributed to the higher degree ofdifferentiation of the mammary gland induced by thehormonal stimulation of pregnancy. In women a majorityof breast cancers that are initially hormone dependentare manifested during the postmenopausal period. Estradiolplays a crucial role in their development and evolution.However, it is still unclear whether estrogens arecarcinogenic to the human breast. The apparentcarcinogenicity of estrogens is attributed to receptor-mediatedstimulation of cellular proliferation. Increasedproliferation could result in turn in accumulation ofgenetic damage and stimulation of the synthesis of growth factors that act on the mammaryepithelial cells via an autocrine or paracrine loop.Alternatively estrogens may induce cell proliferationthrough negative feedback by removing the effect of one or several inhibitory factors present in theserum. Multidisciplinary studies are required for theelucidation of the mechanisms responsible for theinitiation of breast cancer. Understanding of suchmechanisms is indispensable for developing a rationalbasis for its prevention and control.

RAT MAMMARY CARCINOMAS STEROID HORMONES GROWTH FACTORS ANTIESTROGENS ANTIPROGESTINS PREGNANCY DIFFERENTIATION 

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© Plenum Publishing Corporation 1998

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  • Irma H. Russo
  • Jose Russo

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