Spontaneous hyperplastic and neoplastic lesions of the uterus in mice.

A histologic study was done on the spontaneously occurring hyperplastic and neoplastic lesions of the uterus, cervix, and vagina taken from a variety of inbred, hybrid, and backcross female mice. The most commonly observed neoplasm of the endometrium was stromal cell sarcoma, followed by adenocarcinoma, which occurred approximately half as frequently. Hyperplasia was the most commonly observed endometrial lesion occurring either as glandular, stromal, or both and was often cystic with the formation of polyps. Among the benign and malignant lesions other than endometrial, leiomyomas, hemangioendotheliomas and leiomyosarcomas were the most commonly encountered. Lesions in the mucosal cervix and vagina were comparatively rare and were observed in only a few animals. Females with hyperplastic and neoplastic lesions of the uterus, cervix, and vagina in this survey represented a small fraction of the large number of animals necropsied, emphasizing the relative infrequency of these spontaneous lesions in mice.

Mammary tumors and mammary tumor virus expression in hybrid mice of strains C57BL and GR.

Mammary tumorigenesis in genetic crosses between the high mammary tumor incidence GR and the low incidence C57BL mouse strains is highly correlated with murine mammary tumor virus expression in milk. Although the F1 and first backcross females had a mammary tumor incidence which was consistent with a single dominant gene segregation, the tumor incidence in the critical second backcross segregants disproved the single gene hypothesis. Genetic factors were clearly involved in regulation of virus expression which in turn correlated with both tumor incidence and tumor latency; these complex phenotypes are however best explained as threshold or quasicontinuous characters. As predicted from this model, the age specific incidence of mammary tumors showed a broad peak at 14-19 mo of age with no evidence of an early or late phase. Hematopoietic tumors showed no correlation with virus expression or mammary tumorigenesis suggesting different etiologies for these tumors.

Transmission of mammary tumor virus in mouse strain DD: further support for the uniqueness of strain GR.

Outcrosses between high tumor mouse strain DD and low-incidence strains BALB/c and C57BL to produce reciprocal F1 susceptible offspring of both types resulted in high incidences of mammary tumors in (DD female X BALB/c male)F1 and (DD female X C57BL male)F1 females but not in the reciprocal hybrids with DD as the male parent. The finding that transmission of murine mammary tumor virus (MuMTV) in DD was through the milk, as most often observed in mouse strains, further supported the uniqueness of strain GR in which MuMTV is transmitted by either parent.

Mouse mammary tumor virus in hybrids from strains C57BL and GR: breeding test of backcross segregants.

F1 and F2 and first backcross hybrids and second backcross families of the high mammary tumor incidence strain GR and the low incidence strain C57BL were examined for the segregation of mouse mammary tumor viral (MMTV) expression. Although GR has been reported to transmit MMTV as a single dominant gene, several lines of evidence suggest there are multiple genetic factors that influence MMTV expression, MMTV expression as measured by double antibody radioimmunoassay for MMTV p14 segregated in 106 first backcross progeny at a 60:40 ratio, intermediate between what would be expected for either a single or two gene hypothesis. In female second backcross progeny of either male or female first backcross, a heterogeneous pattern of expression was noted that does not fit any simple Mendalian pattern. From an analysis of serial lactations of first backcross and second backcross families, it appears that all hybrid females contain MMTV proviral information that may be expressed either at late lactations or in a variable proportion of progeny mice. These combined results are most consistent with a vertically transmitted genome regulated by multiple factors in these crosses.

Testing the antifertility drug enovid for carcinogenesis in five strains of mice.

In testing for any carcinogenic effect of certain hormones the choice of test strain or strains is extremely important. By selecting several inbred strains one obtains maximum genetic variability offering a greater chance of demonstrating carcinogenesis in regard to a number of organs or tissues. The five strains of mice chosen in this study (C3H/He, C3HfB/He, BALB/cHe, A/He, and C5BL/He) provided a test for effect of Enovid at sterilizing doses on occurrence of mammary tumors, ovarian tumors, hepatomas, cervical and vaginal tumors, adrenocortical adenomas, and hypophyseal tumors. Results indicated a slight inhibitor effect of Enovid on mammary tumors in C3H and adrenocortical adenomas in BALB/c and an even greater inhibiotry effect on hepatomas in C3HfB. No effect on ovarian tumors could be detected in the appropriate test provided by C3HfB. In BALB/c females epithelial lesions of the cervix and vagina were observed in both the treated females and the controls with a slight increase in the group treated with the highest dose. All were small lesions observed only in the histologic section. None had invaded beyond the wall of the vagina, and none had metastasized. None could be classified as a frank carcinoma. In the group treated with the highest dose of Enovid, the lesions showed slightly further progression than in the other groups. The most significant tumorigenic effect of the Enovid was the increase in hypophyseal tumors in the C5BL females at advanced age. Direct extrapolation from one strain to another, from one species to another, from mouse to humans, or from one human being to another would be risky because of genetic differences. Approaches to the problem in human beings are, however, suggested. Because of these observations in mice, it would be well, if possible, to collect hypophyses of women at postmortem who have previously been on birth control pills for some time and send these hypophyses to some central laboratory where they can be examined for any changes that might be attributed to the use of the antifertility drug.

Testing for possible effects of cedar wood shavings and diet on occurrence of mammary gland tumors and hepatomas in C3H-A-vy and C3H-Avy-fB mice.

C3H-A-vy and C3H-A-VY-FB mice transferred from our colony to the laboratory of Dr. J. R. Sabine in Australia had a markedly reduced incidence of both hepatomas and mammary tumors. Sabine and co-workers (J Natl Cancer Inst 50: 1237-1242, 1973) attributed the low incidence of tumors in their laboratory compared to the high incidence in this laboratory to the fact that we routinely use red cedar shavings in the bedding, whereas they use sawdust, predominantly Doublas fir. Results of tests in this laboratory showed that the difference in occurrence of tumors could not be attributed directly to either a difference in diet or bedding. There was no evidence that the cedar shavings were carcinogenic. The animals in Australia on bedding without cedar shavings were not as healthy as our animals, in that they did not grow as well and were infested with ectoparasites; apparently these factors caused the reduced occurrence of tumors.

Effects of the antifertility drug enovid in five strains of mice, with particular regard to carcinogenesis.

PIP: The antifertility drug, Enovid, was tested for possible carcinogenicity in female mice of 5 specially selected strains: BALB/c, C3H, C3HfB, A, and C57BI. Enovid was chosen for testing since it is one of the most widely used oral contraceptives. The 5 strains of mice provided maximum genetic variation in the test animals. The drug was fed at 3 dose levels: 5 mcg/gm, 10 mcg/gm and 20 mcg/gm of food. The lowest dose did not prevent reproduction. The 10 mcg dose prevented some females from reproducing. The 20 mcg dose prevented all females from reproducing. The strains of mice differed in their response to Enovid. Weight gain was reduced in all strains. Effect on life-span varied, partly because of the tumors. Cervical and vaginal lesions showed invasion of the epithelium into the stroma but was limited, with few exceptions to the BALB/c females. In the BALB/c strain these lesions occurred in controls as well, but showed more progression and a higher incidence with the highest dose of Enovid. None of these lesions appeared grossly as tumors and none had extended beyond the vaginal wall or metastasized. They were observed only on histologic sections. Neither ovarian nor mammary gland tumors were increased in any strain. In the C3H strain such tumors seemed to be inhibited. In the C3HfB strain there was some inhibition of hepatomas and in the BALB/c strain some inhibition of adrenocortical adenoma. Chromophobe adenomas of the hypophysis were significantly increased in old C57BI females treated with the highest dose of Enovid. Offspring of Enovid-treated females showed no abnormalities. Enovid increased the occurrence and may have advanced the progression of epithelial lesions of the cervix and vagina of old BALB/c females. A study of the lesions in untreated females of this strain might help the understanding of carcinoma in situ in women and possibly the appearance of adeno-carcinoma of the vagina of young women whose mothers had been treated with stilbestrol during the first trimester to maintain pregnancy. Other neoplasms in this strain were not increased by the Enovid therapy. In the C3H strain mammary tumors were reduced by the Enovid and those that did occur were found later than in controls. Results from experimental animals should be applied to humans with care. Such results are of greatest value in directing attention to certain areas for investigation.^ieng

Inability to predict mammary tumorigenesis in strain A mice from presence of mammary tumor virus or antigen in the milk.

Strain A females were milked and their milk was tested for mammary tumor virus (MTV) by the hyperplastic alveolar nodule test and for MTV antigen by microimmunodiffusion. An attempt was made to correlate these results with later occurrence of mammary tumors in the females. There was not full agreement between the results of the test for the presence of the MTV and those of the test for MTV antigen, and from these results it was impossible to predict accurately whether a specific female would later develop a tumor. It is concluded that, in this strain, factors other than the MTV can be the determinant in whether the individual female will develop a tumor.

Strain C3H-A-vy-fB mice: ninety percent incidence of mammary tumors transmitted by either parent.

Mammary tumorigenesis in C3H-A(vy)fB female mice is not due to milk-borne mammary tumor virus but to factors transmitted at conception. Prominent among these is the A(vy) gene which may increase the virulence or transmissibility of a variant of mammary tumor virus vertically transmitted by either parent, or may increase the tumorigenic response of the mammary tissue. These factors together with the influence of hormones of pregnancy resulted in the high incidence observed.