ApcMin, a mutation in the murine Apc gene, predisposes to mammary carcinomas and focal alveolar hyperplasias.

Abstract

ApcMLU (Min, multiple intestinal neoplasia) is a point mutation in the murine homolog of the APC gene. Min/+ mice develop multiple intestnal adenomas, as do humans carrying germ-line mutations in APC. Female mice carying Min are also prone to develop mammary tumors. Min/+ mammary glands are more sensitive to chemical carcinogenesis than are +/+ mammary glands. Transplantation of mmary celsfromMin/+ or +/+ donors into +/+ hosts demonstrates that the propensity to develop mammary tumors is intrinsic to the Miun/+ mammary cells. Long-term grfts of Min/+ mammar glands also gave rise to focal alveolar hyperplslas, indicating that the presence of the Min mutation also has a role in the development of these lesions.Mutations in the human APC gene have been shown to be involved in both sporadic and familial colon cancer. Individuals carrying germ-line mutations in the APC gene are at risk for the development of adenomatous colon polyps that can progress to cancer (1, 2). In some families there is also an increased risk for desmoid tumors, small intestine tumors, mandibular osteomas, or retinal dysplasias (3).The APC gene is expressed in most tissues that have been surveyed (4, 5), in contrast to the narrow spectrum of tissues overtly predisposed to neoplasia by mutations in this gene. A limited spectrum of neoplastic transformation is also observed for other broadly expressed genes in which mutations can predispose to cancer, such as RB (6), P53 (7), and NF (8 10). The mammary glands from donors ofeach genotype, +/+ orMin/+, were pooled on ice, enzymatically treated, and processed to produce a monodispersed epithelial cell suspension as described (13). Recipient females were injected with 2.5 x 104 mammary cells in each oftwo sites in the white intrascapular fat pad. Any one animal received either Min/+ or +/+ cells.At 5 weeks after transplantation, animals from the set that received the Min/+ cells and from the set that received the +/+ cells were each randomly assigned to one of three treatment groups: 7,12-dimethylbenz[a]anthracene (DMBA), ENU, or control. DMBA at 1 mg (Eastman Kodak) in 0.2 ml of sesame oil was delivered by intubation weekly for 6 weeks. ENU was delivered by a single i.p. injection at a dose of 200 mg/kg (body weight). Untreated animals were followed as controls.The untreated and ENU-treated mice received a graft of a whole pituitary gland from a B6 female under the left kidney capsule 8-9 weeks after cell transplantation (3-4 weeks after ENU treatment). DMBA-treated mice received pituitary grafts 3 weeks after the final DMBA treatment.At 1-to 2-week intervals for 52 weeks, all mice were palpated for the presence oftumors at both the transplant site and the 10 intact in situ mammary glands of the host animals. Whenever possible, tumors were resected and the animals were kept for further observation. Moribund animals were sacrificed, and complete necropsies were performed. Any tumors or growths were recorded and fied in buffered 10%o formalin, embedded, sectioned, and stained for histologic...

Use of MMTV-Wnt-1 transgenic mice for studying the genetic basis of breast cancer

“…Mutations in APC, a negative regulator of the Wnt signaling pathway, have been reported to confer an increased risk for development of breast cancer in Ashkenzi Jews (Redston et al, 1998;Woodage et al, 1998). Min mice, which carry a nonsense mutation at one APC locus, also have increased risk for mammary carcinomas after carcinogen treatment (Moser et al, 1993(Moser et al, , 1995. With the use of additional TG mice, it will be interesting to determine if deregulated expression of other components of the Wnt-1 signaling pathway, such as over-expression of bcatenin and inactivation of E-cadherin, also induce mammary tumors.…”

Dysregulated expression of β-catenin marks early neoplastic change in Apc mutant mice, but not all lesions arising in Msh2 deficient mice

“…First, desmoid tumours have been reported to occur spontaneously in Apc mutant mice (Shoemaker et al, 1997;Smits et al, 1998). Second, Apc Min heterozygotes show an increased susceptibility to mammary carcinoma both spontaneously and following genotoxic stress such as carcinogen treatment or X irradiation (Moser et al, 1993(Moser et al, , 1995van der Houven et al, 1997). Finally, Apc heterozygosity on a p53 null background has been shown to strongly predispose to pancreatic neoplasia (Clarke et al, 1995).…”

Frequent mutations of the Trp53, Hras1 and β-catenin (Catnb) genes in 1,3-butadiene-induced mammary adenocarcinomas in B6C3F1 mice

“…Although mutations in HRAS and CTNNB1 are rarely found in human mammary malignancies, enhanced HRAS expression in both protein and mRNA levels has been observed (Thor et al, 1986). Activation of the Wnt/b-catenin pathway has also been implicated in mammary carcinogenesis (Tsukamoto et al, 1988;Moser et al, 1993;Lin et al, 2000).…”

“…Activation of the Wnt signaling pathway has also been implicated in mammary carcinogenesis (Tsukamoto et al, 1988;Moser et al, 1993;Lin et al, 2000). The ultimate result of Wnt pathway activation is the accumulation of free monomeric Catnb and in turn the activation of its target genes such as cyclin D1 (Ccnd1) and Myc (Lin et al, 2000;Korinek et al, 1997;Morin et al, 1997;Tetsu et al, 1999;He et al, 1998).…”