Role of Neuroendocrine System in Regulation of Mammary Tumors in Different Species

Abstract

Mammary tumors are the most common type of neoplasm in the female rat, mouse, dog and man, but these tumors differ in their origin, morphology, invasiveness, degree and kind of hormone dependency, and in other characteristics. Mammary tumors are believed to originate from ductal tissue in women and rats, from pre-neoplastic alveolar nodules in mice, and from epithelial, fibrous and other tissues in the dog. Most spontaneous mammary tumors in aging female rats and dogs appear to be benign, whereas a high percentage of mammary tumors in mice and women are malignant. There are marked contrasts in the reproductive cycles among these 4 species which can differentially influence mammary tumor development and growth.Prolactin and estrogen appear to be the 2 most important hormones involved in mammary tumorigenesis in the rat, mouse and perhaps women, but there is no clear evidence that either hormone is essential for mammary tumor development in the dog. Prolactin secretion is under the direct control of the hypothalamus, and the ovaries are under the indirect control of the hypothalamus via the gonadotropins. Hypothalamic regulation of pituitary function appear to be similar among the different mammalian species, and can be altered by administration of many central acting drugs, hormones and environmental stimuli.In the rat and mouse, a deficiency of prolactin, estrogen or both can inhibit development of spontaneous or carcinogeninduced mammary tumors. An excess of prolactin, estrogen, or estrogen and progesterone, also can inhibit mammary tumorigenesis in the rat and perhaps in the mouse. Existing mammary tumors in the rat require prolactin and estrogen for continued growth, but in mice mammary tumors soon become autonomous and independent of hormones. The pituitary and ovaries are important in development of breast cancer in women, although a definite role for prolactin remains to be demonstrated. Ovariectomy or early pregnancy in women are associated with reduced breast cancer incidence, but only about \(\frac{\hbox{$\scriptstyle 1$}}{\hbox{$\scriptstyle 3$}}\) of all breast cancer patients are responsive to endocrine treatments such as ovariectomy, adrenalectomy, hypophysectomy, or high estrogen or androgen therapy. In dogs, ovariectomy is most effective in reducing mammary tumor incidence when performed before the first estrous cycle, and ovariectomy gradually becomes less effective in preventing mammary tumors with subsequent estrous cycles. A role for prolactin in dog mammary tumors has not been demonstrated.Prolonged estrogen treatment in rats and mice induces mammary cancers, but only in the presence of the pituitary. There is considerable evidence that an important component of mammary tumor induction by estrogen is stimulation of prolactin secretion. A prolonged increase in prolactin secretion by appropriate hypothalamic lesions or administration of neuroleptics also can induce mammary cancers in female mice, and hasten development and increase the number of benign mammary tumors in female rats. In women there is no convincing evidence that prolonged intake of estrogens or steroid contraceptive pills increase the incidence of breast cancer, and there is some evidence to the contrary. Prolonged use of reserpine which increases prolactin secretion has been reported to be associated with increased numbers of breast cancers in women, but there are contrary reports as well. A definite role for prolactin in breast cancer in women has not been established. In dogs progesterone rather than estrogen appears to be important for mammary tumor induction. Prolonged administration of predominantly progestogenic steroids to dogs results in the appearance of mammary nodules or tumors, and this is not associated with an increase in prolactin secretion. Thus the dog appears to differ markedly from other species in hormonal influences on mammary tumorigenesis.Key wordsMammary tumorsRatMouseDogManNeuroendocrine control