CANCER RESEARCH VoLvm~ 19 DECEMBER 1959 NUMBER 11 Mammary Tumors of the Rat" A Review R. L. NOBLE AND J. H. CvT'rs (Dept. of Medical Research, Collip Laboratory, University of Western Ontario, London, Canada) Mammary tumors in the rat have been studied ORIGIN AND CHARACTERISTICS in detail by only a few groups of workers. There is, A. SPONTANEOUS MAMMARY TUMORS however, a considerable amount of information on 1. Incidence.--Spontaneous tumors in rats al- the subject contained in isolated papers and scat- lowed to live their normal life span are relatively tered throughout the scientific literature. Appar- common, and in large series of animals from 10 to ently, no previous attempt has been made to re- 60 per cent may show tumors of some kind (13, view this field of interest. In the past, the attention 119). The proportion of these which were confined of geneticists, virologists, endocrinologists, and to mammary tissue has varied in different reports biologists has been focused on the mammary tu- and with different strains of rats; however, mam- mors of the mouse, and a vast literature has ac- mary tumors have been the common type of tu- cumulated in which these tumors are characterized mor affecting the over-all tumor incidence. In the very exactly. The rat has been somewhat neglected August strain of rats 30 per cent of all tumors were in this concentration of effort on the smaller spe- of mammary origin, whereas in the Copenhagen cies, although it would appear worthy of greater strain only 5.6 per cent were similarly situated and more serious attention. The need for a tabula- (13). In another large series of rats of mixed tion of rat data may be appreciated from the ap- strains, 18 per cent of 521 spontaneous tumors pearance in 1954 of a paper in Science, containing were located in the breast (9). Of a group of 150 no references, entitled "Successful Transplanta- female Sprague-Dawley rats with an average life tion of an Apparently Benign Neoplasm." A rat span of 760 __+_21 days, mammary tumors ac- fibroadenoma apparently was transplanted suc- counted for 95 per cent of the total tumors found cessfully. This achievement should not have been and were present in 54 per cent of the animals. In a unexpected in view of Loeb's report in 1902 of group of 40 males, 12.5 per cent showed tumors of autotransplantation and in 1916 of homoiotrans- which only two were of mammary origin, giving a plantation of similar tumors in rats. general average of 88 per cent for both sexes. In Rat mammary tumors have many points of in- two colonies of rats of the Wistar strain mammary terest and differ from those of the mouse in many tumors accounted for 77 per cent of all tumors. In ways. Histologically, both benign and malignant females 281 of 839 (68 per cent) showed mammary tumors occur spontaneously in the rat, or may be tumors, whereas 42 of 129 males (32 per cent) had similar tumors (119). It is apparent that from 6 to induced by a number of means. No viral factors 77 per cent of all tumors occurring spontaneously have been demonstrated, and most rat tumors are in rats may be of the mammary gland and that curiously sensitive to hormone manipulation. females may show a ratio of approximately 6 to 1 Their possible value in chemotherapeutic screen- when compared with males. ing of hormone derivatives has only recently re- 2. Malignant tumors of epithelial or mesodermal ceived attention. All these considerations will be origin.--Malignant, spontaneous mammary tu- pointed out in the following review. mors in the rat have been classified as adenocar- Received for publication June 11, 1959. cinoma, solid carcinoma, cystadenocarcinoma, 1125 Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 1959 American Association for Cancer Research. 11~6 Cancer Research Vol. 19, December, 1959 papillary carcinoma, and, rarely, squamous-cell mors. Similarly, Bullock and Curtis (9) examined carcinoma. Fibrosarcomas are more frequently en- 94 tumors of the breast and noted eight adenomas, countered, and mixed tumors combining adeno- one adenolipoma, and 78 fibroadenomas or fibro- carcinoma and squamous-cell cancer have been mas (93.4 per cent benign tumors). In 150 described. Thus, of 41 malignant spontaneous tu- Sprague-Dawley female rats, 90 per cent of 7~ mors encountered in a series of rats of mixed breast tumors were classed as benign--one adeno- strains, s per cent were classed as of epithelial ma, 46 adenofibromas, and eighteen fibromas (16). origin (seven adenocarcinoma, one squamous-cell Curtis, Bullock, and Dunning (13), after examin- carcinoma, and two adeno-acanthoma), 12 per ing over 30,000 rats from seven distinct strains, cent as mixed tumors (three sarcoma with adeno- found a total tumor incidence of 9.6 per cent, and, carcinoma and two with added squamous-cell car- of these, mammary fibroadenoma contributed cinoma), and 59 per cent as fibrosarcoma (28). 12.8 per cent. Of the 6410 female rats reaching an Bullock and Curtis (9), in examining 94 spontane- age of 14 months (considered to be the minimum ous breast tumors occurring in 489 rats of mixed time of appearance), 0.9 per cent showed benign origin, noted two cystadenocarcinoma with squa- fibroadenomas. Of 219 female Wistar rats bearing mous epithelium, two carcinosarcomas, and three mammary tumors and averaging 650 days of age, adenomas exhibiting sarcomatous change. Dun- 206 were classed as benign tumors. The growth ning and Curtis (23), in a study of 15,625 rats de- rate of the spontaneous fibroadenomas varied rived from twenty generations of pure strain Co- greatly. Of twenty tumors, eleven increased 2-10 penhagen 2331 and Fischer 344 rats and their times their original volume in 90 days (119). reciprocal F1 and backcross hybrids, also observed Metastases have not been observed. 82 mammary tumors. Of these, only two were 4. Factors influencing incidence of spontaneous malignant: one was an adenocarcinoma and one a tumors.- fibrosarcoma. Age: The age of the rat, as might be sus- In 149 mammary tumors arising in random- pected, influences the incidence of spontaneous tu- bred Albany strain of hooded rats, only one adeno- mors found at any time. Studies in which the ani- carcinoma was found (8, 144). In 468 rats of mals have been allowed to live their normal life Wistar origin exhibiting 273 mammary tumors, span have been the most informative. It was noted eleven mammary adenocarcinomas and two sar- that 80 per cent of fibroadenomas developed in comas were noted (119). Similarly, of 94 spontane- female Wistar rats between 64 and 128 weeks of ous tumors of the breast occurring in 489 rats only age, whereas carcinomas occurred somewhat ear- two were classed as cystadenocarcinoma and two lier in life (119). In the Albany strain of rats, be- as carcinosarcoma (9). Probably the highest inci- nign tumors arose chiefly between 52 and 88 weeks dence of spontaneous adenocarcinoma of the of age, although three tumors were noted in rats breast has been reported in 150 female rats of the only 20 weeks of age (144). In a comparison of Sprague-Dawley random-bred strain. Over an seven different strains of rats, fibroadenomas were average life span of 760 + 21 days, mammary tu- encountered in 0.9 per cent of 6410 females reach- mors were found in 72 rats (54 per cent) and, of ing 14 months of age (13). these, seven (10 per cent) were classed as adeno- Sex: As may be noted from the preceding dis- carcinoma. The over-all incidence of carcinoma of cussion, the sex of the rat may markedly influence the breast in these female rats therefore was 4.6 the occurrence of mammary tumors. Female ani- per cent. On the other hand, a smaller group of 40 mals were much more predisposed to this type of male animals of the same strain developed only tumor, although all types of tumors have been en- two mammary tumors (16). Metastases from spon- countered in males. The relative frequency of taneous malignant tumors have occasionally been mammary tumors has been low in males, possibly noted (8, 28). from 1 to 6 per cent of all mammary tumors. 3. Benign tumors of epithelial or mesodermal While exact experiments are not available, the origin.--Benign spontaneous mammary tumors implication is strong that the cause of the higher constitute a much larger group than do the preced- incidence in females is related to the influence of ing. Adenoma and adenolipoma have been de- the sex hormones. As will be seen later, estrogens scribed occasionally, but fibroadenoma and fibro- and progesterone may stimulate growth or be es- ma are apparently the most common tumor. Of the sential for successful takes of transplanted spon- 82 mammary tumors found in 15,625 rats pre- taneous mammary tumors, particularly the fibro- viously referred to (I~8), two were adenomas, two adenomas. On the other hand, it may be noted that adenolipomas, five fibromas, and 21 fibroadenomas mammary tumors induced by sex hormones are ba total of 93.7 per cent benign mammary tu- usually multiple, and practically all are classed as Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 1959 American Association for Cancer Research. NOBLE AND CuTTs--Mammary Tumors of the Rat: Review 1127 carcinoma. Some of the earlier workers were im- has been described as being discovered in 1938 on pressed with the possible role of a disturbed hor- the lower abdomen of a pregnant albino rat. It ap- mone balance as a cause of spontaneous tumors in parently regressed in size during lactation but the rat (70, 96) and believed that forced breeding grew rapidly again after the young were weaned.