Chronic energy intake restriction (CEIR) reduces mouse mammary tumor virus (MMTV)-induced mammary tumors in C3H/Ou mice. Fewer than 10% of C3H/Ou mice developed mammary tumors during 88 wk of study when subjected to CEIR regardless of calorie source (fat vs. carbohydrate). By contrast, 100% of mice fed ad libitum diets relatively high in fat or carbohydrate or a commercial diet developed tumors by 35-40 wk. MMTV proviral DNA transcription was shown to be activated in spleen, liver, lung, kidney, small intestine, and mammary gland of mice consuming these diets ad libitum. By contrast, these messages were suppressed by CEIR in all tissues analyzed except spleen. MMTV proviral messages in liver and mammary gland increased with age in full-fed mice and were suppressed by CEIR.These frndings suggest that the nutritional regulation ofMMTV proviral DNA expression is tissue-specific. In CEIR mice the suppressed MMTV proviral DNA transcripts in mammary gland and liver increased with time in association with the delayed onset of mammary tumors. Mammary tumorigenesis in C3H mice is associated with integration of MMTV proviral DNA, which appears to activate a putative mammary tumor protooncogene, int-i. CEIR apparently decreases the frequency of viral reintegration adjacent to the int-i gene and thus inhibits expression of int-I and probably an initiation step in mammary tumorigenesis. Expression of other putative protooncogenes, int-2 and ras, in liver tissue was also reduced by CEIR. These frndings indicate that both initiation and promotion of mammary tumorigenesis are influenced by CEIR in C3H/Ou mice. §To whom reprint requests should be addressed. 2385The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
To analyze simultaneously the influence attributable to calorie consumption level and percentage of dietary fat on the spontaneous development of mammary adenocarcinoma, virgin female C3H/Ou mice were separated into five dietary groups. Four groups of mice were fed purified diets either ad libitum (16-18 kcal/mouse/day) or restricted 40% in calorie consumption (10-11 kcal/mouse/day), and diets contained either 4.5%, 7.5%, 67%, or 68% calories from fat. Mice that consumed isocaloric diets developed breast malignancy at a comparable pace. Consuming a diet in which fats were present only at levels sufficient to satisfy the threshold requirement of essential fatty acids, 4.5-7.5% of the total calories, or alternatively where dietary fat represented greater than 67% of the total calories consumed, did not significantly alter the tendency for breast tumor development. The pace and frequency with which tumors occurred reflected the host's level of calorie consumption. Mice consuming a high caloric diet, low or high in fat, tended to have a shortened latency to breast tumor formation, an increased incidence of breast tumors, elevated serum prolactin levels, elevated levels of antibodies to mouse mammary tumor virus, and elevated circulating immune complex levels.
Chronic energy-intake restriction inhibits mouse mammary tumor virus (MMTV)-induced mammary tumors in C3H/Ou mice by >90%. We That chronic energy-intake restriction (CEIR) delays or inhibits the development of experimental mammary adenocarcinoma has become increasingly evident (1-3). Although diet, body weight, 'and breast tumorigenesis had been strongly associated from critical analysis of human epidemiological data, little was known of the underlying mechanisms that conferred the protective effect (4). The C3H/Ou mouse is a model strain for investigating the biology of spontaneous mammary tumorigenesis. Mammary adenocarcinomas occur in 50%o offemale C3H/Ou mice within 30-35 weeks of age (5).To explain the mechanisms of tumorigenesis, an insertionalmutagenesis model of the milk-transmitted type-B retrovirus mouse mammary tumor virus (MMTV) near the Int-i locus and subsequent clonal growth of the mutant' cells have been reported (6). In addition, hormones, 'genetic make-up, and immunological status may be important in the initiation and/or development of mammary tumors.Prior studies have shown that calorie restriction (40%) delays dramatically the development of mammary tumors in C3H mice (3). Fewer precancerous hyperplastic alveolar nodules (HAN) are found, MMTV expression is suppressed, and blood prolactin levels are lower (1-3) in mice subjected to CEIR. Because blood prolactin levels appear affected by calorie restriction and prolactin levels in vitro apparently regulate MMTV expression (7), alterations of prolactin levels with calorie restriction may be important in breast tumorigenesis for their mammotrophic effects, acute somatogenic effects, and for action on proviral expression (3,7,8).Development of HAN is suppressed and tumor formation is reduced among C3H mice treated daily with dopamine analogs such as 2-bromo[a]ergocryptine (CB-154), which lower blood prolactin (9). Conversely, multiple adenohypophyseal grafts, which are principally prolactin-secreting, to adreno-ovariectomized C3H mice shorten the interval to median tumor incidence (10); expression of MMTV in the tissues, however, was not investigated in the latter studies.To further our understanding of the mechanisms by which calorie restriction reduces risk for mammary cancer, virgin C3H/Ou mice were fed a semi-purified diet either ad libitum or restricted 40% in calorie consumption (CEIR), and basal serum prolactin levels were experimentally reduced or elevated. Serum prolactin was elevated by grafting two adenohypophyses under the renal capsule. Serum prolactin was reduced by i.p. injection of the dopamine analog octahydrobenzo[g]quinoline (CV205-502). Levels of proviral mRNA expression in mammary gland, serum prolactin levels, and prevalence of HAN lesions were then assessed under different conditions of dietary calorie level and prolactin levels. Our data'indicate a crucial role for prolactin in the early expression of MMTV mRNA in vivo, regardless of calorie levels that otherwise inhibit or permit mammary adenocarcinoma developme...
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