836 



THE CARCINOGENIC STIMULUS 



I I 



(Murray, 1928) induces mammary cancer in male mice of inbred strains in which 

 a high incidence of mammary cancer occurs in the females. From the mammary 

 cancers of high tumor strains, as well as from the normal mammary gland, there 

 can be obtained a filterable agent which is important in influencing mammary 

 carcinogenesis (Bittner, 1942). Depriving female mice of this agent (by foster- 



MAMMARY CARCINOGENESIS 



ESTROGEN 

 VIRUS 



^ 



MAMMARY CANCER 



WITH 

 MTA* 



EARLY APPEARANCE 

 HI6H% 



(2) 



EST 

 CHE 

 GE 



TROGEN — ^ 



EMICAL** ^^ 



NETIC -^ 



'3 



WITHOUT EARLY APPEARANCE 

 MAMMARY CANCER MTA HIGH % 



DEVIATED HISTOLOGY 



WITHOUT '-*'''E APPEARANCE 

 MAMMARY CANCER MTA DECREASED % OR NONE 

 USUAL HISTOLOGY 



(4) 



ESTROGEN — 

 PITUITARY 

 GRAFTS ~ 



GENETIC (?)- 



LATE APPEARANCE 

 WITHOUT 

 » MAMMARY CANCER MTA HIGH % 



USUAL HISTOLOGY 



'mTA' MAMMARY TUMOR AGENT 

 ^CARCINOGENIC HYDROCARBON 



Fig. 28. This figure indi- 

 cates the involvement and 

 relationship of various fac- 

 tors in mouse mammary 

 carcinogenesis. In certain 

 inbred high mammary can- 

 cer strains (i) estrogenic 

 hormone and a virus (mam- 

 mary tumor agent) operate 

 together, but only in mice 

 of appropriate genetic con- 

 stitution. The virus can be 

 deleted by foster-nursing; 

 if the foster-nursed mice are 

 treated with a carcinogenic 

 hydrocarbon {e.g., methyl- 

 cholanthrene) mammary 



cancer may be induced (2). Such mammary cancers do not reveal the mammary tumor 

 agent by bioassay. Certain sublines of foster-nursed high mammary cancer strains develop 

 mammary cancer late in life, and no agent can be demonstrated biologically, raising the 

 question concerning necessity of the mammary tumor agent for mammary tumorigenesis ; 

 administration of the mammary cancer agent accelerates the onset of mammary cancer. 

 That hormonal factors may dominate in mammary carcinogenesis is demonstrated (4) 

 by the effect of pituitary isografts on mammary tumor induction. Functional pituitary 

 grafts will cause mammary cancer to appear in lines of mice presumably without the mam- 

 mary tumor agent. The primary secretion of pituitary isografts is lactogenic horiuone. 



nursing) may remarkably depress the incidence of mammary cancer. Cell-free 

 breast milk and mammary tumor extracts have been considered to contain a virus 

 which is the etiologic agent in the appropriate genetic and hormonal environment 

 (Bittner, 1942). Administration of cell-free extracts of mammary cancers may 

 restore a high incidence of mammary cancer in lines of mice deprived of the agent 

 by foster-nursing (Bittner, 1942). 



That hormonal factors per se may induce mammary carcinogenesis independent 

 of a viral agent has been suggested by a number of experiments (Fig. 28). The 

 estrogen-induced mammary cancers of rats seem not to be influenced in their de- 

 velopment by a filterable factor analogous to the mouse mammary tumor agent 

 (Dunning and Curtis, 1952). Certain lines of mice freed of the milk-agent by foster- 

 nursing develop mammary cancers, but relatively late in life (Heston et al., 1950). 

 When males of one agent-free subline of the C3H strain were injected with estrogen- 

 ic hormone, mammary cancers appeared (Heston and Deringer, 1954). From 

 these neoplasms a mammary tumor agent was not obtained utilizing methods 

 which ordinarily reveal it (Heston and Deringer, 1954; Miihlbock, 1956). Pituitary 

 isografts may cause mammary cancer to develop in female mice lacking (by 

 available tests) the mammary tumor agent (Miihlbock, 1956). 



