Host genetic background effect on the frequency of mouse mammary tumor virus-induced rearrangements of the int-1 and int-2 loci in mouse mammary tumors

Abstract

The frequency with which int-I and int-2 are rearranged in mouse mammary tumors by mouse mammary tumor virus (MMTV)-induced insertional mutagenesis is a consequence of the host genetic background. In 75 % of C3H mammary tumors, int-i is rearranged by MMTV insertion, whereas only 30% of BALB/cfC3H tumors contain a virus-induced rearrangement of int-1. This difference is significant (P < 0.005) and could not be accounted for by the potentially additive effect of the genetically transmitted Mtv-1-encoded virus in C3H mice. Similarly, MMTV-induced rearrangement of the int-2 gene in mammary tumors of the Rlll mouse strain (59%) occurred at a significantly (P < 0.025) higher frequency than in BALB/cfRlll (25%) mammary tumors. Moreover, in BALB/cfRlll mammary tumors, there is evidence that rearrangement of int-i and int-2 does not occur independently (P < 0.025). These results suggest that the long history of inbreeding for high tumor incidence of C3H and Rlll mouse strains has selected for the fixation of host mutations which either complement the action of the particular int gene or affect the sensitivity of specific subpopulations of mammary epithelium to infection by particular strains of MMTV.

Mouse mammary‐tumor virus activates Fgf‐3/Int‐2 less frequently in tumors from virgin than from parous mice

“…A more consistent finding in the present and previous surveys is that over half of the mammary tumors analyzed showed activation of more than one Znt-gene (Gray et al, 1986;Peters et al, 1986, 19896;Mester et al, 1987;Pathak et al, 1987;Marchetti et al, 1991). For example, in the multiparous RIII and BALBlcfBR6 mice described here, 13 of the 24 tumors co-expressed Wnt-1 and Fgf-3, in line with our earlier observations for BR6 mice (Peters et al, 1986).…”

“…Taken together, these data imply that in breeding females the same virus on different genetic backgrounds activates Wnt-1 and Fgf-3 with the same or similar frequencies. Previous reports comparing C3H and RIII mice with their fostered BALB/cf counterparts have reached different conclusions and have reported much lower frequencies of Znt-gene activation (Pathak et al, 1987;Marchetti et al, 1991). One possible explanation is that these earlier studies relied primarily on DNA polymorphisms to detect proviral insertions and may have underestimated the true frequencies of Int-gene expression.…”

“…Although few studies have compared Int-gene activation within different categories of tumors from a single mouse strain, it is interesting that multiparous C3H and C3Hf mice, in which there is a natural preponderance of hormone-independent lesions, show a similarly low frequency of Fgf-3 activation (Pathak et al, 1987;Etkind, 1989;Marchetti et al, 1991;Schwartz et al, 1992). These results lend support to the idea that Fgf-3 expression is primarily associated with a pregnancydependent phenotype and reinforce the parallels between the naturally occurring tumors and transgenic models.…”

“…Thus, Wnt-1 is the predominant target in strains of mice that develop pregnancy-independent tumors, such as C3H, whereas Fgf-3 is more frequently activated in strains that are noted for pregnancydependent lesions, such as GR, RIII and BR6 (Gray et al, 1986;Peters et al, 1986;Mester et al, 1987;Pathak et al, 1987;Etkind, 1989;Morris et al, 1990;Marchetti et al, 1991;Schwartz et at., 1992). In the latter mice, it is common to find that more than one Int gene has been activated by MMTV, suggesting a stepwise selection for cells that acquire a more autonomous phenotype (Peters et al, 1986;Mester et al, 1987;Marchetti et al, 1991). A possible explanation would be that Fgf-3 expression per se can give rise only to hormonedependent hyperplasia and that further events, including insertional mutagenesis by MMTV, may be required to achieve hormone-independence.…”

Mouse Mammary Tumor Virus Carrying a Bacterial supF Gene Has Wild-Type Pathogenicity and Enables Rapid Isolation of Proviral Integration Sites

“…The cellular proto-oncogenes found to be transcriptionally activated or directly mutated by MMTV proviral insertion mutations are often members of either the Wnt or fibroblast growth factor family but may also include Notch4/int3, Cyp19/int5, Int6, and Int41 (5-7, 15, 19, 20, 25-27, 30). The frequency with which genes are targeted in tumors varies with the genetic background of the host (21). Studies of MMTV insertional mutagenesis have been very useful in discovering novel genes involved in mammary tumorigenesis: of the 10 MMTV-activated or -mutated genes reported thus far, 7 were first discovered during such studies.…”