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

Abstract

Wnt-1 was ®rst identi®ed as a protooncogene activated by viral insertion in mouse mammary tumors. Transgenic expression of this gene using a mouse mammary tumor virus LTR enhancer causes extensive ductal hyperplasia early in life and mammary adenocarcinomas in approximately 50% of the female transgenic (TG) mice by 6 months of age. Metastasis to the lung and proximal lymph nodes is rare at the time tumors are detected but frequent after the removal of the primary neoplasm. The potent mitogenic e ect mediated by Wnt-1 expression does not require estrogen stimulation; tumors form after an increased latency in estrogen receptor a-null mice. Several genetic lesions, including inactivation of p53 and over-expression of Fgf-3, collaborate with Wnt-1 in leading to mammary tumors, but loss of Sky and inactivation of one allele of Rb do not a ect the rate of tumor formation in Wnt-1 TG mice.

The Wnt pathway regulator DKK1 is preferentially expressed in hormone-resistant breast tumours and in some common cancer types

“…Consequently, interaction with the transcription factor TCF delivers positive signals for cell proliferation (reviewed in Rothbacher and Lemaire, 2002;Brennan and Brown, 2004). Interestingly, in 1982, Nusse and Varmus (1982 identified the first Wnt gene as being a mammary oncogene, and several members of the Wnt family have been linked to cancer development, especially of the breast (reviewed in Li et al, 2000). Surprisingly, low levels of membranous b-catenin expression have been associated with significantly worse outcomes (Dolled-Filhart et al, 2006), which contradicts other studies (Lin et al, 2000;Chung et al, 2004).…”

Estrogen receptor positivity in mammary tumors of Wnt-1 transgenic mice is influenced by collaborating oncogenic mutations

“…Thus, we hypothesized that these additional genetic alterations might affect the ER status of the resulting tumors. We and others have reported several collaborating genetic changes in tumorigenesis in Wnt-1 TG mice, including mutations of H-Ras, loss of Pten or p53, and overexpression of Neu (Donehower et al, 1995;Li et al, 2000Li et al, , 2001Podsypanina et al, 2004). When tumors that bore a Ras-activating mutation (G12E, G13V, Q61L and Q61R), determined by sequencing tumor DNA, were compared with those that did not, both ER and PR levels were similar by Western blotting (Figure 2a).…”

Stabilization of β-catenin induces lesions reminiscent of prostatic intraepithelial neoplasia, but terminal squamous transdifferentiation of other secretory epithelia

“…Over expression of Wnt genes is causally linked with mammary carcinogenesis (Li et al, 2000), as well as some degree of squamous metaplasia in mice (Harold Varmus, personal communication). We propose that induction of mammary adenocarcinoma in Wnt overexpressing mice requires the engagement of pathways in addition to b-catenin.…”

“…Furthermore, activation of Wnt genes is associated with mammary carcinoma in mice (for review see Li et al, 2000). Wnt signaling ultimately leads to the stabilization of b-catenin, by preventing its phosphorylation at critical exon 3 encoded serine and threonine residues and its subsequent degradation (for reviews see Bienz and Clevers, 2000;Lau and Clevers, 2001).…”