Ill 



VIRUSES AND CANCER 85I 



do they develop mammary cancer (Tannenbaum, 1940). It was concluded that 

 the altered hormonal status inhibits carcinogenesis (Huseby et al., 1945). Cystine 

 deficient mice similarly fail to respond to otherwise adec|uate viral and genetic 

 factors (White and Andervont, 1943), but exogenous estrogen may cause mammary 

 carcinogenesis to proceed in one-half the mice fed inadequate amounts of cystine 

 (White and White, 1944). 



That the mammary tumor agent is the etiological virus in the sense that infectious diseases 

 are virus-caused is open to question on the basis of the following evidence. In one foster- 

 nursed high mammary tumor line (C3Hf) the incidence of mammary cancer in females is 

 38% (Heston et al., 1950). The cancers appear significantly later in life than in genetically 

 similar mice which possess the mammary tumor agent. C3Hf mammary cancers do not 

 test positive for the agent; males of this line develop mammary cancer when given estrogenic 

 hormone, and in such tumors no agent is demonstrable by the usual bioassay (Heston and 

 Deringer, 1954). Similarly the agent has not been revealed in mammary tumors induced 

 by methylcholanthrene in females of either pure lines made agent-free by foster-nursing 

 (Bittner and Kirschbaum, 1950) or of strains which do not possess the agent (Dmochowski 

 and Orr, 1949; Figs. 37, 39-41). However, virus like particles have been observed by 

 Bernhard and Oberling (1957) in electron micrographs of mouse mammary cancers 

 which do not reveal the agent by biological methods. 



Miihlbock (1956) has reared agent-free mice which were not only nursed by 

 low tumor mothers, but which developed in their uteri (ovum transfer). One third 

 of such agent-free females developed late mammary cancer. The incidence was 

 increased to 100% if the ani?nals carried functional pituitary isografts (from the same inbred 

 strain). Such grafts cause hyperstimvdation of the mammary gland. 



With a favorable hormonal (functioning ovaries and pituitary isografts) and 

 genetic status, favoring the development of mammary cancer (100% incidence), 

 onset of the disease is accelerated by the introduction of the mammary tumor 

 agent (Muhlbock, 1956). The virus would, from these experiments, appear to be an 

 accelerator of and not an essential etiological agent for mouse mammary cancer. It is possible, 

 however, that the difference in the time of onset of mammary cancer is dependent 

 upon amount of agent, and not presence or absence. 



Multiple factors are involved in mouse mammary carcinogenesis. Under certain 

 circumstances it appears that the agent may be deleted and still mammary cancer 

 occurs (Heston et al., 1950). In other instances withdrawal of the agent 

 results in an extremely low incidence of mammary cancer (Bittner, 1936b). The 

 influence of the agent depends upon the potency of other factors, including a 

 genetically determined environment favoring the propagation of the agent itself 

 (Heston et al., 1956). 



Apparently carcinogenic hydrocarbons may substitute for the mammary tumor 

 agent in accelerating the onset of mammary cancer in agent-free mice (Kirsch- 

 baum et al., 1946; Andervont and Dunn, 1953). Such induced tumors usually 

 show squamous metaplasia (Kirschbaum, 1949). Since a mammary tumor agent 

 could be extracted from neither these tumors, nor histologically similar tumors 

 occurring in aged females of strains without the agent, it was suggested that this 

 type of mammary histology might be correlated with agent-free tumorigenesis. 

 Although agent-free tumors are characteristically variable microscopically, 

 squamous metaplasia is not an essential structural feature (Heston et al., 1950; 



Lileralure p. 870 



