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Induction of Mammary II. Histological Cancer with Methylcholanthrene* Similarity between Carcinogen-induced Tumors and Certain Mammary Neoplasms Occurring Spontaneously ARTHURKIRSCHBAUM, PH.D., M.D. (From the Department of Anatomy, University of Minnesota Medical School, Minneapolis, Minnesota) The onset of mammary cancer has been accel erated in female mice of the dba stock by the ad ministration of carcinogenic hydrocarbons (4, 8, 11). When the milk-agent was excluded by fosternursing or by hybridization (e.g., F! hybrid crosses between dba males and females of a second stock lacking the milk-agent), it was still possible to in duce mammary cancer by administering methylcholanthrene (7, 10). In the low mammary cancer NHO stock, methylcholanthrene was carcinogenic for the mammary gland (13). Carcinogen-induced adenocarcinomas of the mouse mammary gland are characterized by a large amount of squamous epithelial metaplasia, whether the carcinogen is dissolved in benzene and applied to the skin overlying the mammary gland (8, 10), injected intravenously (7), administered intranasally in oil (8), or applied subcutaneously at sites far removed from the development of mammary cancer (6). This histologie picture could be interpreted as a specific result of the keratinizing influence of the carcinogenic hydrocarbon; keratinized masses are to be found within only 10 per cent of the adenocarcinomas arising spontane ously in stocks which possess the milk-agent and exhibit a high incidence of mammary cancer (3). In a report comparing the histology of spon taneous and carcinogen-induced mammary cancer it was concluded that the spontaneous and induced tumors are dissimilar in both their final structure and their histogenesis (10). The spontaneous mammary tumors studied had arisen in mice pos sessing the milk-agent. Recently the author has studied mammary tumors arising spontaneously in hybrid crosses between females of the low mam mary cancer NH1 strain and males of subline 212, * This, investigation has been aided by grants from the Jane Coffin Childs Memorial Fund for Medical Research, the National Cancer Institute, and the Cancer Fund of the Gradu ate School of the University of Minnesota. strain dba. The histologie structure of these tu mors was found to be similar to that observed in the carcinogen-induced mammary cancers. This material is being presented, and its possible sig nificance is discussed. MATERIALS AND METHODS Untreated breeding female mice of the NH stock were observed for spontaneous mammary cancer. In approximately 500 females only one mammary tumor has been seen (Fig. 1). XH mice TABLE1 OCCURRENCE OFMAMMARY TUMORS INHYBRID MICEOFTHENH ANDDF)A-(212) STRAINS Genetic constitution NHXD F,* NHDXNHDF, NHDX D back-cross Total or range * D indicates No. of mice 18 15 9.9. 55 No. with mammary cancer 3 3 1 Age of mammary cancer (months) 30-34 22-30 22-26 22-34 dba-Ã-lÃ-. were crossed with animals of the dba strain (subline 212), so that the maternal influence was al ways provided by the NH stock. The groups and numbers of hybrid mice studied are presented in Table 1. Hybrids all were breeding animals and were ob served for the occurrence of mammary tumors. Those neoplasms which appeared were studied histologically. Comparison was made between the sections of these tumors and of mammary tumors in our collection (a) arising spontaneously in mice with the milk-agent, Strong A, dba, and (C3H X dba) FI hybrids, and (6) induced by methyl cholanthrene in mice with, e.g., dba-212, and with1NH mice obtained from Dr. L. C. Strong, of Yale I'niversity School of Medicine, in the eighth inbred generation in 1941 and now in the twenty-fifth inbred generation. 93 Downloaded from cancerres.aacrjournals.org on August 9, 2017. © 1949 American Association for Cancer Research. - - * • FIGS. I TO 3 Downloaded from cancerres.aacrjournals.org on August 9, 2017. © 1949 American Association for Cancer Research. KIRSCHBAUM—Mammary Cancer with Methylcholanthrene. out the milk-agent, e.g., Zb mice (10) and the progeny of dba-212 mice fostered by a Zb female. Methylcholanthrene was dissolved in l)enzene (0.25 per cent solution) and was painted on the skin three times weekly for from eighteen to fifty times, the site of painting being varied to delay the development of skin tumors (4). OBSERVATIONS AND DISCUSSION The incidence and age of appearance of mam mary tumors in the hybrid mice are presented in Table 1. The incidence of mammary tumors was low. This, together with the late appearance, sug gests that the milk-agent is not present in the NH stock. The typical appearance of these tumors is il lustrated in Figs. 1 and 2. Histologically they are indistinguishable from methylcholanthrene-induced cancers (Fig. 3). The large amount of squamous metaplasia differentiated them from the spontaneous mammary adenocarcinomas of high cancer stocks, in which islands of keratinized epithelium are found in only a small per cent (9). Unfortunately, tumors of F! hybrid mice of the dba X NH cross were not studied histologically. Such mice would be genetically identical with the FI hybrids studied here and would also possess the milk-agent. Unpublished data from another laboratory also reveal that, in spontaneous mammary tumors aris ing in very old hybrid mice without the milkagent, considerable amounts of squamous epithe lial tissue are present (11). Other observations in dicate that spontaneous tumors appearing in the absence of the milk-agent are not necessarily of this histologie type (12) and may not be essentially different histologically from tumors associated with the milk-agent (6). The microscopic structure of mouse mammary cancer described and illustrated here (adenocarcinoma with squamous metaplasia) can be corre lated with etiology other than the milk-agent (in one case carcinogenic hydrocarbon and in the other unknown). The carcinogen-induced neo plasms of the mammary gland of mice resemble certain spontaneous tumors of this species, but these are not the spontaneous adenocarcinomas usually studied and described for mice. They are tumors not ordinarily seen, since they appear in very old females of populations in which the mammary tumor incidence is low, that is, females without the milk-agent. FIG. 1.—Mammary tumor arising spontaneously in the strain XH female. The only mammary cancer which has been seen in this stock. Large amount of squamous epithelial meta plasia. Mag. X70. FIG. 2.—Mammary tumor arising in an Fi hybrid female (NHXdba). Both squamous epithelial tissue and epithelium II 95 Studies are in progress (in collaboration with Dr. John Bittner) to ascertain whether a mam mary tumor-inciting agent can be extracted from these tumors characterized histologically by squamous metaplasia. SUMMARY Spontaneous mammary adenocarcinomas in hy brid mice of certain genetic constitution, and pre sumably without the milk-agent, exhibited a pro nounced degree of squamous metaplasia. The structure of these tumors was similar to that seen regularly in methylcholanthrene-induced mam mary cancers. It is suggested that this histologie type of mammary tumor may be indicative of de velopment independent of the milk-agent. REFERENCES 1. ANDERVONT, H. B., and DUNN,T. B. Mammary Tumors in Mice Presumably Free of the Milk Agent. J. Nat. Cancer Inst., 8:227-233, 1948. 2. BITTXER, J. J. Inciting Influences in the Etiology of Mammary Cancer in Mice. Am. A. Adv. Sc. Res. Conf. Cancer. 1945, pp. 63-96. 3. DUNN,T. B. Morphology and Histogenesis of Mammary Tumors: A Symposium on Mammary Tumors in Mice, pp 13-38. Am. A. Adv. Sc., 1945. 4. ENGELBRETH-HOLM, J. Acceleration of the Development of Mammary Carcinoma in Mice by Methylcholanthrene. Cancer Research, 1:109-112, 1941. 5. GARDNER,W. U. Personal communication, 1945. 6. HESTON,W. I". Personal communication. Presentation at meeting of American Association for Cancer Research. 1948. 7. KIRSCHBAUM, A. Unpublished observations. 8. KIRSCHBAUM, A., LAWRASON, F. D., KAPLAN,H. S., and BITTNER,J. J. Influence of Breeding on Induction of Mammary Cancer with Methylcholanthrene in Strain dba Female Mice. Proc. Soc. Exper. Biol. & Med., 56:141-142, 1944. 9. KIRSCHBAUM, A., and STRONG,L. C. Influence of Carcino gens on the Age Incidence of Leukemia in the High Leukemia F Strain of Mice. Cancer Research, 2:841-845, 1942. 10. KIRSCHBAUM, A., WILLIAMS,W. L., and BITTNER,J. J. Induction of Mammary Cancer with Methylcholanthrene. I. Histogenesis of the Induced Neoplasm. Cancer Research, 6:354-362, 1946. 11. MIDER, G. B., and MORTON,J. J. Effect of Methylcho lanthrene on Intent Period of Breast Tumors in Dilute Brown Mice. Proc. Soc. Exper. Biol. & Med., 42:583-584, 1939. 12. ORR, J. W. Mammary Carcinoma in Mice Following the Intranasal Administration of Methylcholanthrene. J. Path. & Bact., 55:483-488, 1943. 13. STRONG,L. C., and WILLIAMS,W. L. A Genetic Analysis of the Induction of Tumors by Methylcholanthrene. III. Local and Remote Induction of Carcinoma of the Mam mary Gland. Cancer Research, 1:886-890, 1941. exhibiting the acinar arrangement of mammary adenocarcinoma present. Mag. X150. FIG. 3.—Mammary tumor induced with methylcholanthrene in a Zb female (C3H lacking the milk-agent). Histo logically, carcinogen-induced tumors are identical with mammary tumors arising spontaneously in females without the milk-agent. Mag. X70. Downloaded from cancerres.aacrjournals.org on August 9, 2017. © 1949 American Association for Cancer Research. Induction of Mammary Cancer with Methylcholanthrene: II. Histological similarity between carcinogen-induced tumors and certain mammary neoplasms occurring spontaneously Cancer Res 1949;9:93-95. Updated version E-mail alerts Reprints and Subscriptions Permissions Access the most recent version of this article at: http://cancerres.aacrjournals.org/content/9/2/93 Sign up to receive free email-alerts related to this article or journal. To order reprints of this article or to subscribe to the journal, contact the AACR Publications Department at [email protected]. To request permission to re-use all or part of this article, contact the AACR Publications Department at [email protected]. Downloaded from cancerres.aacrjournals.org on August 9, 2017. © 1949 American Association for Cancer Research.