Activation of endogenous MMTV proviruses in murine mammary cajncer induced by chemical carcinogen

Abstract

A study was undertaken to determine whether activation of expression of silent endogenous mouse mammary tumor virus (MMTV) proviruses may occur during tumor induction by a chemical carcinogen. A series of transplantable mammary tumors induced in BALB/c mice by treatment with dimethylbenz(alpha)anthracene (DMBA), pituitary isograft, or both was examined. The results obtained suggest that chemical carcinogens may induce mammary tumors through more than one pathway. Two of 9 tumor lines produced virus-specific products at levels above those observed during the course of normal mammary gland development. One tumor contained high levels of MMTV-specific envelope [3.8 kilobase (kb)] and genomic length (8.9 kb) RNAs. This tumor expressed core- and envelope-related proteins detectable by immunoblotting (including p28, gp52, and gp36), displayed an acquired provirus with a restriction map different from those of described exogenous MMTV strains, and contained abundant virus particles. The other tumor that expressed high levels of MMTV gene products contained envelope-specific (3.8 kb) and long-terminal-repeat-specific (1.6 kb) messages but no full-length RNA. It exhibited an aberrant 39 kDa, envelope-related protein, but no virus particles. Methylation data implicated the usually silent endogenous Mtv-8 provirus as the source of the abnormal envelope protein. None of the tumors expressed RNA from the putative mammary oncogenes, int-1 or int-2. We propose that chemical carcinogens may activate different cellular genes by mutation and that, in a subset of DMBA-induced mammary tumors, the target genes include endogenous MMTV proviruses that are normally not expressed. The effect on provirus expression varies from tumor to tumor, but is stable over passage of a given tumor. MMTV may be of etiological importance in the genesis of those DMBA-induced tumors which contain high levels of MMTV-specific products, but its action in the BALB/c system is not mediated through enhanced expression of the int-1 or int-2 preferred integration regions.

The mouse mammary tumor virusenvgene is the source of a CD8+T-cell-stimulating peptide presented by a major histocompatibility complex class I molecule in a murine thymoma

“…Furthermore, with the exception of M11024 discussed above, the known MMTV env sequences do contain the AFV8 peptide. Thus the explanation for why normal spleen cells fail to generate the AFV8͞K b complex could lie in differential regulation of the MMTV transcription as noted in the mammary gland and in T-cell tumors (36,61). It is also possible that the processing of the env protein to the AFV8 peptide may not occur efficiently in splenic APCs.…”

Regulation of the oncogenic phenotype by the nuclear body protein ZC3H8

“…Mouse mammary tumor cell lines were derived from independently arising tumors in BALB/cV mice carrying the MMTV cV [ 20 , 21 ]; or BALB/c mice carrying a chemically induced mammary tumor expressing a variant MMTV strain of unknown origin [ 22 ]. Tumors were excised, minced and grown in DMEM supplemented with 50% fetal bovine serum (FBS), decreased in 10% increments at each passage to a final 10% FBS.…”