The Occurrence of Benign and Malignant Mammary Lesions in Rats Treated with Crystalline Estrogen*

The relationship of ovarian hormones to the development of the breast and, logically, to mammary cancer appeared clearly outlined in the results of early castration experiments on mice. Prepuberty ovariectomy inhibited normal growth of the breast, with the consequence that females of strains with mammary tissue highly susceptible by heredity to spontaneous malignant alteration failed to develop this lesion. Nevertheless, later experiments indicated that this generalization needs modification, for Woollcy, Fekete, and Little (48) demonstrated that the adrenal gland is capable of assuming the function of the ovary in animals spayed within :z 4 hours after birth. Estrogens in mice.--With the demonstration that mammary cancer can be induced in animals by various estrogenic preparations, a firm foundation seemed assured for the theory that cancer of the breast is a local manifestation of excessive stimulation of this organ by one of the substances responsible for its physiologic control, or of an abnormal stimulation determined by some endocrine dyscrasia. Proof for these hypotheses has been sought for preeminently in mice. It quickly became apparent from the observations of Lacassagne ( 2 9 ) , Gardner and his coworkers (18), Burrows (7), Cramer and Horning (9), Suntzeff and his associates (43), Bonser, Stickland, and Connal (6), Twombly (46), Taylor and Waltmarf (45), and others that treatment of mice with estrogens gave rise to a higher percentage of mammary cancers than would occur normally, and at an earlier age in females of stocks genetically susceptible to the disease in a greater or lesser degree. Males of these same strains, which if untreated did not have tumors of the mamma, also developed cancer if they received estrogen. In the absence of the hereditary factor, however, the female sex hormone induced no mammary cancers even in females. It is worthy of note that exceptions to the former sequence have been discovered. Thus, according to Bischoff and his coauthors (3) the mammary tissue of Marsh mice, though highly susceptible by heredity to the development of cancer, resisted the effect of injected estrogen. Excellent general reviews of much of the literature have been contributed by Lacassagne (3o), Cramcr (8), Gardner (W), Allen (I) , and Loeb (3I). Estrogens in rats.--Species other than the mouse have been less widely employed to elucidate the hormonal mechanisms related to mammary cancer. The rat, rarely the host of spontaneous malignant tumors of the mamma, also proved resistant to excessive exogenous estrogenic stimulation in the experiments of Heiman and Krehbiel (28), Emge (I4), Druckrey ( io) , Silvestroni (39), and Grumbrecht (26). McEuen (32), on the other hand, observed an occasional cancer of the mamma, among other neoplasms, in rats given estrogen and painted with tar. Mammary cancer developed more readily in animals that