Transgenic mouse models of human breast cancer

Hutchinson, John N.; Muller, William J.

doi:10.1038/sj.onc.1203970

Cited by 131 publications

(88 citation statements)

References 82 publications

(77 reference statements)

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“…For some genes, such as c-Myc and ErbB2, overexpression of either in the mouse mammary epithelium alone is su cient to induce tumor formation (Guy et al, 1992;Hutchinson and Muller, 2000;Leder et al, 1986;Mueller et al, 1997). Then, why do these changes have to occur in Brca1-associated tumors together and what are their roles?…”

Section: Discussionmentioning

confidence: 99%

Multiple genetic changes are associated with mammary tumorigenesis in Brca1 conditional knockout mice

et al. 2001

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Germline mutations in the tumor suppressor gene BRCA1 predispose women to breast cancer, however somatic mutations in the gene are rarely detected in sporadic cancers. To understand this phenomenon, we examined mouse models carrying conditional disruption of Brca1 in mammary epithelium in either p53 wild type (wt) or heterozygous backgrounds. Although a p53 +/7 mutation signi®cantly accelerated tumorigenesis, both strains developed mammary tumors in a stochastic fashion, suggesting that multiple factors, in addition to p53 mutations, may be involved in Brca1 related tumorigenesis. A unique feature of Brca1 mammary tumors is their highly diverse histopathology accompanied by severe chromosome abnormalities. The tumors also display extensive genetic/molecular alterations, including overexpression of ErbB2, c-Myc, p27 and Cyclin D1 in the majority of tumors, while they were virtually ERa and p16 negative. Translocations involving p53 were also identi®ed which lead to abnormal RNA and protein products. In addition, we generated cell lines from mammary tumors and found that the cells retained many of the genetic changes found in the primary tumors, suggesting that these genes may be players in Brca1-associated tumorigenesis. Despite their distinct morphology, all cultured tumor cells were Tamoxifen resistant but highly sensitive to Doxorubicin or girradiation, suggesting that these methods would be e ective in treatment of this disease. Oncogene (2001) 20, 7514 ± 7523.

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Section: Discussionmentioning

confidence: 99%

Multiple genetic changes are associated with mammary tumorigenesis in Brca1 conditional knockout mice

et al. 2001

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“…This result raises the intriguing possibility that PTP1B may positively contribute to the progression of these cancers by way of activation of Src. It will be interesting to determine the effects of introducing the PTP1B null background into transgenic models of breast cancer (39).…”

Section: Discussionmentioning

confidence: 99%

The role of protein tyrosine phosphatase 1B in Ras signaling

Dubé

Cheng

Tremblay

2004

Proc. Natl. Acad. Sci. U.S.A.

129

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Protein tyrosine phosphatase (PTP) 1B has been implicated as a negative regulator of multiple signaling pathways downstream of receptor tyrosine kinases. Inhibition of this enzyme was initially thought to potentially lead to increased oncogenic signaling and tumorigenesis. Surprisingly, we show that platelet-derived growth factor-stimulated extracellular-regulated kinase signaling in PTP1B-deficient cells is not significantly hyperactivated. Moreover, these cells exhibit decreased Ras activity and reduced proliferation by way of previously uncharacterized pathways. On immortalization, PTP1B-deficient fibroblasts display increased expression of Ras GTPase-activating protein (p120RasGAP). Furthermore, we demonstrate that p62Dok (downstream of tyrosine kinase) is a putative substrate of PTP1B and that tyrosine phosphorylation of p62Dok is indeed increased in PTP1B-deficient cells. Consistent with the decreased Ras activity in cells lacking PTP1B, introduction of constitutively activated Ras restored extracellular-regulated kinase signaling and their proliferative potential to those of WT cells. These results indicate that loss of PTP1B can lead to decreased Ras signaling, despite enhanced signaling of other pathways. This finding may in part explain the absence of increased tumor incidence in PTP1B-deficient mice. Thus, PTP1B can positively regulate Ras activity by acting on pathways distal to those of receptor tyrosine kinases.

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“…The c-MYC gene is amplified and/or overexpressed in a high proportion of human breast cancer, although the frequency of these alterations varies greatly (Liao and Dickson, 2000). ErbB2 is also amplified and subsequently overexpressed in 20-30% of human breast cancers, and overexpression of ErbB2 is correlated with a poor clinical prognosis of both node-positive and node-negative tumors (Hutchinson and Muller, 2000). The Cyclin D1 gene is amplified in 15-20% of human breast cancers (Bieche et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

EN2 is a candidate oncogene in human breast cancer

et al. 2005

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Only a few critical oncogenes have been identified in the more commonly occurring cases of sporadic breast cancer. We provide evidence that EN2 is ectopically expressed in a subset of human breast cancer and may have a causal role in mammary tumorigenesis. Nontumorigenic mammary cell lines engineered to ectopically express En-2 have a marked reduction in their cycling time, lose cell contact inhibition, become sensitive to 17-AAG treatment, fail to differentiate when exposed to lactogenic hormones and induce mammary tumors when transplanted into cleared mammary glands of syngeneic hosts. RNA interference studies suggest that EN2 expression is required for the maintenance of the transformed phenotype of a human breast tumor cell line.

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Transgenic mouse models of human breast cancer

Cited by 131 publications

References 82 publications

Multiple genetic changes are associated with mammary tumorigenesis in Brca1 conditional knockout mice

Multiple genetic changes are associated with mammary tumorigenesis in Brca1 conditional knockout mice

The role of protein tyrosine phosphatase 1B in Ras signaling

EN2 is a candidate oncogene in human breast cancer

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