Suppression of spontaneous mammary tumorigenesis despite mtv‐1 gene expression in hybrid and backcross c3h‐avyfb × c3h/sm mice

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Abstract
Mouse mammary tumor virus (MMTV)‐specific RNA and antigen content of normal and neoplastic mouse mammary tissue were measured in strains C3H/Sm and C3H‐AvyfB, in C3H‐AvyfB♀ × C3H/Sm♂ F1 hybrids and in (C3H‐AvyfB × C3H/Sm) × C3H/Sm♂ backcross segregants. Good correlation between MMTV antigen expression in lactating mammary glands and mammary tumor incidence was observed in the parental mouse strains. The high‐mammary‐cancer strain C3H‐AvyfB (90%) had consistently high levels of MMTV antigen in the mammary glands and tumors, whereas mammary tissues from low‐mammary‐cancer subline C3H/Sm (1.6%), whether normal or neoplastic, had little or no detectable MMTV antigen. In contrast, MMTV RNA content of normal C3H/Sm mammary tissue was consistently as high as or higher than corresponding levels in C3H‐AavfB females. These molecular data, along with the relative mammary tumor incidences, suggest that the endogenous MMTV provirus expression gene Mtv‐l present in C3H mice is fully expressed in the C3H‐AvyfB subline but is silent or more probably absent in the C3H/Sm subline. Our earlier genetic crosses between C3H‐AvyfB and C3H/Sm mice were conducted to determine the effect of the Avy gene on mammary tumorigenesis during its segregation in back‐cross (BC) females produced from matings of the F1 hybrid females with C3H/Sm males. Our mammary tumor incidence data presented in the accompanying paper strongly suggested the possibility that C3H/Sm mice possessed a dominant genetic factor(s) which specifically attenuated the tumorigenic effects of the Avy and Mtv‐l genes on the mammary gland without affecting the Avy gene's enhancement of liver tumorigenesis and obesity. Examination of MMTV RNA and antigen content in (C3H‐AvyfB × C3H/Sm) hybrid and BC females showed that the expression of MMTV antigen was completely suppressed in the agouti (AA) BC females. However, yellow F1 (AvyA) and yellow (AvyA) BC females continued to express MMTV antigen in their mammary glands even though mammary tumor incidence was significantly depressed. MMTV RNA levels were similar in all F1 and BC females regardless of the presence or absence of the Avy gene. Mammary tumor incidence was reduced in all the BC females (whose genome is 3/4 derived from C3H/Sm) relative to the F1 females (whose genome is only 1/2 derived from C3H/Sm) suggesting that more than one gene is involved in the suppression of spontaneous mammary tumor development. Cessation of translational expression of endogenous MMTV occurred only in the agouti (AA) BC females, suggesting an association between this phenomenon and the agouti locus of C3H/Sm. Evaluation of the relative MMTV RNA content of nucleic and cyto‐plasmic fractions from C3H/Sm mammary tissues strongly suggests that transport and/or processing of MMTV RNA is defective in these mice. This defect probably accounts for the absence of detectable MMTV antigens in C3H/Sm and agouti (AA) BC mammary tissues and tumors and may contribute to the observed reduction in mammary tumor incidence.