Hormonal regulation of murine mammary tumor virus RNA expression during mammary tumorigenesis in BALB/c mice

Abstract

The effects of glucocorticoids and prolactin on murine mammary tumor virus (MuMTV) RNA expression in preneoplastic outgrowth lines and mammary tumors in BALB/c mice were investigated. Hyperplastic alveolar nodules (HAN) and a ductal hyperplasia (DH) are induced in virgin BALB/c mice by prolonged hormonal stimulation or treatment with 7,12-dimethylbenz(a)anthracene or both. Mice bearing HAN or DH outgrowth lines and mammary tumors that arose from the outgrowth lines were treated with glucocorticoids or prolactin. MuMTV RNA was quantitated by hybridization with a representative complementary DNA probe specific for MuMTV RNA. Prolactin treatment did not increase MuMTV RNA in the BALB/c HAN or DH outgrowth lines or tumors. MuMTV RNA increased after glucocorticoid treatment in the C3, C4, and C5 HAN outgrowth lines and in tumors that arose from the Dl, D2, C4, and C5 HAN and CD8 DH outgrowth lines. No increase in MuMTV RNA with glucocorticoid treatment was observed in the Dl or D2 HAN outgrowth line, in the CD8 DH outgrowth line, and in tumors that arose from the C3 HAN outgrowth line. The ability of glucocorticoids to stimulate MuMTV expression was specific since the response was dose dependent and specific for glucocorticoid hormones. Glucocorticoid treatment did not increase the level of type C viral RNA in the majority of hormoneor 7,12-dimethylbenz(a)anthracene-induced HAN outgrowth lines or tumors. These observations suggested that glucocorticoids may influence MuMTV expression during mammary tumorigenesis in BALB/c mice. Murine mammary tumorigenesis is a multistage process that is influenced by several factors, including the mouse mammary tumor virus (MuMTV), hormones, and carcinogens (1, 2,22). BALB/c mice, which have a low incidence of spontaneous mammary tumors (22), contain five to nine copies of the endogenous, germinally transmitted MuMTV per diploid cell (1, 21). MuMTV RNA was low or undetectable in BALB/c mammary glands from breeding females and in spontaneous mammary tumors (14, 26, 27). In contrast, glands and tumors from the high-tumor-incidence strain BALB/cfC3H, which contain an exogenous milk-transmitted virus designated MuMTV-S (1), had high amounts of MuMTV RNA (26, 27).

Quantitative of murine mammary tumor virus-related RNA in mammary tissues of low- and high-mammary-tumor-incidence mouse strains

“…It should be noted, however, that our results discussed above contrast with the previous findings of Pauley et al (12,13) and Michalides et al (6, 7), which indicated that BALB/ c hormonally induced mammary tumors contain significantly greater quantities of MuMTV RNA than do normal lactating mammary glands. However, great variation in the quantity of MuMTV-related RNA has been found in cells obtained from BALB/c mammary tumors (12,13). Our data show that there is significant variation in the apparent amount of MuMTV-like RNA in both mammary glands and tumors, depending upon the method of extraction.…”

“…Furthermore, the quantity of MuMTV-related RNA, which was barely detectable when method 1 was used for extraction, was significantly increased if method 2 was used for obtaining RNA from mammary glands or tumors. This result suggests that the presence of RNase in both BALB/c mammary glands and tumors may have resulted in the failure to report measurable MuMTVrelated RNA levels by investigators using procedures similar to method 1 (1,2,6,7,12,13,20). Our results are in general agreement with those of Michalides et al (6, 7), Dudley et al…”

“…All mammary tumors arising spontaneously from this strain, however, appear late in the life of the mouse at 16 to 24 months of age. The frequency of mammary tumor incidence, as well as the time of appearance of the tumors, can be increased through the use of chemical carcinogens (2,6,11) or by hormonal induction with pituitary isografts (4,7,8,12,13). The involvement of MuMTV in the production of BALB/c spontaneous mammary tumors has not been established, and even in sublines with a tumor incidence of 35%, no evidence of MuMTV antigens or type B oncornaviral particles could be detected in milk or tumor extracts, nor could biological evidence of tumorigenic activity be established when the extracts were inoculated into various mouse strains (8).…”