A new site of integration for mouse mammary tumor virus proviral DNA common to BALB/cf(C3H) mammary and kidney adenocarcinomas.

Abstract

The BALB/cf/Cd substrain of mice, developed by inbreeding and selection, shows a 70% incidence of spontaneous kidney adenocarcinomas. Initially foster‐nursed on C3H mothers, these mice no longer produce mammary tumors, but there is evidence that mouse mammary tumor virus (MMTV) is involved in the formation of these renal carcinomas. We identified a chromosomal region called int‐41, representing a locus interrupted by the integration of an exogenous MMTV provirus in a BALB/c mammary tumor. We found a DNA rearrangement and transcriptional activation in the domain specified by the int‐41 probe in one primary kidney adenocarcinoma. A 5.2‐kb int‐41 specific mRNA was detected in the kidney tumor cell line established from a transplantable renal adenocarcinoma. This mRNA hybridized with MMTV and int‐41 specific probes suggesting that it is a hybrid molecule composed of MMTV‐LTR sequences covalently linked to host cell RNA. This mRNA was strongly stimulated by the presence of glucocorticoid hormone in the culture medium. Our data are compatible with the hypothesis that the int‐41 chromosomal domain is involved in the neoplastic transformation of epithelial cells from different organs.

Identification of a new common provirus integration site in gross passage A murine leukemia virus-induced mouse thymoma DNA.

“…Because of this chromosomal location, Gin-i is distinct from int-i and int-2, which map on mouse chromosomes 15 (34,39) (47). The restriction map of the Gin-i region is distinct from those of Mlvi-3 (51, 52) and int4i (17). Moreover, we found no homology of Gin-i with 16 oncogenes tested, and no oncogene has yet been reported to map on mouse chromosome 19.…”

“…In a high proportion of avian leukosis virus-induced tumors, proviruses have been found to be inserted close to c-myc (20,33,37) and to c-erbB (15), leading to an increased transcription of these oncogenes. Two regions, int-i (34,35) and int-2 (12,38), in DNA of mouse mammary tumor virus-induced mouse mammary carcinoma and one region, int41 (17), in DNA of mouse mammary tumor virus-induced kidney adenocarcinoma have been reported to represent common regions for provirus integration, whose transcription was activated by these insertions. In MuLV-induced T-cell lymphoma, c-myc (7,31,43,49) and a putative new tyrosine kinase oncogene, tck (58), have been shown to be activated by provirus insertion.…”

Two regions of the mouse mammary tumor virus long terminal repeat regulate the activity of its promoter in mammary cell lines.

“…Its association with T-cell leukemia (27, 28), thymomas (1), and kidney adenocarcinomas (17,47) in the same species has also been documented. Although the MMTV genome encodes a large open reading frame of unknown function (15), this gene has not been associated with oncogenic activity, and the virus is currently thought to induce cell transformation by integrating in the vicinity of cellular proto-oncogenes (int genes), causing their deregulated expression (11,37).…”

BST-2/tetherin is overexpressed in mammary gland and tumor tissues in MMTV-induced mammary cancer

“…MMTV-mediated neoplastic transformation of mammary glands and development of mammary cancer follows after APCs and T cells have been infected by MMTV and trafficked to mammary gland, infecting mammary epithelial cells (Ross, 2010). Induction of mammary tumors by MMTV is mediated by proviral integration into the host mammary epithelial cells and activation of protooncogenes, such as Wnt genes, Fgf family genes, Notch family genes, IntH/Int5, Int6, and Int41 (Callahan and Smith, 2000; Durgam and Tekmal, 1994; Garcia et al, 1986; Gray et al, 1986; Marchetti et al, 1995), and about 33 common insertion sites recently identified in a high-throughput MMTV insertional mutagenesis screen (Szabo et al, 2005). …”