PTEN deficiency: a role in mammary carcinogenesis

Cancer is a multi-step process involving the mutation of genes regulating cell proliferation, differentiation, and survival, leading to escape from normal tissue boundaries and sustained angiogenesis [2]. Given the plethora of genetic alterations observed in primary breast cancers, it has been difficult to establish which are involved in initiation, progression and metastasis. Despite often significant difficulties in the interpretation of their relevance to human disease, mouse models have provided experimental tools to investigate genetic pathways altered in breast cancer. Furthermore, the interbreeding of different TG or gene-deficient mouse models can reveal the potential for cooperation between different signaling pathways.Mammary tumors induced following mouse mammary tumor virus (MMTV) infection have revealed oncogenes involved in murine mammary tumorigenesis. Random insertion of proviral MMTV DNA into mouse mammary epithelial cells results in insertional mutagenesis and oncogenic activation of various genes, including those of the Wnt, Fgf, and notch families, and eIF-3p48. The first proto-oncogene to be cloned from MMTV-induced mammary cancers was Wnt-1 [3], a member of a family of secreted cysteine-rich glycoproteins, which controls cell fate/patterning through stabilization of β-catenin and activation of the downstream transcription factor T cell factor (TCF/LEF). MMTV-Wnt-1 TG mice develop mammary tumors histopathologically similar to human breast cancers. These mice develop extensive mammary hyperplasia, and tumors progress to adenocarcinomas in a temporally predictable manner [4]. Although overexpression of Wnt-1 has not been observed in human breast cancers, several downstream components of the Wnt signaling pathway are deregulated in human cancers, including adenomatous polyposis coli, β-catenin, c-Myc, and cyclin D1 [5]. Moreover, overexpression of a stable transcriptionally active β-catenin in a mouse mammary model induced multiple aggressive mamma