Inactivation of Apc perturbs mammary development, but only directly results in acanthoma in the context of Tcf-1 deficiency

Gallagher, Ronald; Hay, Trevor; Méniel, Valérie S.; Naughton, Catherine; Anderson, Thomas; Shibata, Hiroyuki; Ito, Masaki; Clevers, Hans; Noda, Tetsuo; Sansom, Owen J.; Mason, John O.; Clarke, Alan R.

doi:10.1038/sj.onc.1205892

Cited by 37 publications

(38 citation statements)

References 54 publications

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“…We see a similar lack of effect for deficiency of Tcf-1 in the intestine. This is in marked contrast with the synergy we have previously observed in the mammary gland between loss of Apc and Tcf-1, which converts a metaplastic phenotype into one of rapid adenocarcinoma formation [20].…”

Section: Analysis Of Downstream Components and Potential Modifiers Ofcontrasting

confidence: 67%

Cancer genetics: mouse models of intestinal cancer

Clarke

2007

Biochemical Society Transactions

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The capacity to model cancer within the mouse has advanced significantly in recent years. Perhaps the most notable technical gains have been in the development of techniques that allow the temporal and spatial control of gene expression, so that it is now possible to regulate target genes in the tissue of choice and at a given time [Maddison and Clarke (2005) J. Pathol. 205, 181-193; Shaw and Clarke (2007) DNA Repair 6, 1403-1412; Marsh and Clarke (2007) Expert Rev. Anticancer Ther. 7, 519-531]. We have used these approaches to study tumorigenesis in the murine intestine. Loss of function of the tumour-suppressor gene Apc (adenomatous polyposis coli) has been associated with the development of both human and murine neoplasia, principally those of the intestinal epithelium. However, as Apc has been implicated in multiple cellular functions, the precise mechanisms underlying these associations remain somewhat unclear. I review here the use of an inducible strategy to co-ordinately delete genes from the adult murine epithelium. This approach has allowed a characterization of the direct consequences of inactivation of gene function. For Apc, these include failure in the differentiation programme, failure to migrate, aberrant proliferation and the aberrant induction of apoptosis. Transcriptome analysis of this model has also identified potential new targets for therapeutic intervention, such as Sparc (secreted protein acidic and rich in cysteine), deficiency of which, we have now shown, suppresses adenoma formation. Finally, we have been able to address how other genes modulate the consequences of Apc loss. Thus we show that there is little effect following loss of cyclin D1, Tcf-1 and p53, but that there are marked differences following loss of either c-Myc or Mbd2. The models therefore allow us to define the earliest events associated with carcinogenesis in the intestine.

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Section: Analysis Of Downstream Components and Potential Modifiers Ofcontrasting

confidence: 67%

Cancer genetics: mouse models of intestinal cancer

Clarke

2007

Biochemical Society Transactions

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“…Osteopontin (Opt) staining was detected in mammary tumor sections (e, arrow) in addition to sections from a lung metastasis (g) keratin expression. A role for b-catenin in squamous metaplasia induction has been described in two mammary-specific transgenic mouse systems that resulted in stabilized b-catenin (Gallagher et al, 2002;Miyoshi et al, 2002). In addition, the formation of squamous metaplasias in response to b-catenin accumulation has been described in transgenic mice that overexpress the Wnt pathway proteins in mammary tissue (Rosner et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

“…Stabilization of b-catenin in the mammary epithelium of transgenic mice results in the appearance of squamous metaplasia (Gallagher et al, 2002;Miyoshi et al, 2002). Profuse squamous metaplasias found in WAP-HGF tumors (Figure 7a, arrows) and lung metastasis (Figure 7b, arrow) prompted us to investigate whether b-catenin was also stabilized in cells from WAP-HGF tumors.…”

Section: Accumulation Of B-catenin In Areas Of Squamous Metaplasiamentioning

confidence: 99%

Targeted expression of HGF/SF in mouse mammary epithelium leads to metastatic adenosquamous carcinomas through the activation of multiple signal transduction pathways

2003

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Overexpression of hepatocyte growth factor (HGF), also called scatter factor (SF), and its receptor c-Met are associated with poor prognosis for cancer patients. In particular, breast cancer cells can produce HGF that acts in a paracrine as well as in an autocrine manner. Therefore, HGF and c-Met are putative targets for cancer therapy. To explore HGF/c-Met signaling in breast cancer, we have generated transgenic mice expressing HGF specifically in mammary epithelium under the transcriptional control of the whey acidic protein (WAP) gene promoter. WAP-HGF transgenic females developed hyperplastic ductal trees and multifocal invasive tumors after several pregnancies, some of which progressed to lung metastases. Tumors produced HGF and displayed phosphorylated c-Met, which correlated with increased Akt as well as c-myc activation. A high growth rate, as demonstrated by Ki67 nuclear antigen staining, and a lack of progesterone receptor were characteristic of the tumors. Immunohistochemical analysis revealed areas of osteopontin (Opn) expression in WAP-HGF tumors and lung metastases in agreement with a previously reported role for Opn in invasive growth. We suggest that these mice may serve as a new breast cancer model for the evaluation of the effects of unscheduled HGF expression in breast cancer.

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“…Modeling loss of Apc in other tissues has begun to explain this phenomenon. Within both the developing mammary gland and the renal epithelium, Apc loss alone provides a selective disadvantage where cells undergoing cre-mediated recombination and Apc deletion being lost (20,21), whereas loss of Apc in the developed mammary leads to transdifferentiation to squamous metaplasia, which is resistant to undergoing transformation (20). In these scenarios, Apc is lost, C-Myc is up-regulated, and yet the cells do not have a selective advantage, underscoring that the precise cellular context is crucial to the outcome an Apc mutation.…”

Section: Implications and Questions Raisedmentioning

confidence: 99%

C-Myc Is a Critical Mediator of the Phenotypes of Apc Loss in the Intestine

Wilkins

Sansom

2008

Cancer Research

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The Adenomatous polyposis coli (Apc) gene is mutated in up to 80% of sporadic colorectal cancers. After Apc loss, there is deregulation of the Wnt signaling pathway and transactivation of T-cell factor/leukemia enhancing factor target genes such as C-Myc. This review focuses on recent data highlighting the importance of the C-Myc oncogene and its transcriptional targets in establishing all of the phenotypes caused by the deletion of the Apc tumor suppressor gene within the intestinal epithelium. The importance of investigating Apc and C-Myc gene function in the correct tissue context is also discussed. [Cancer Res 2008;68(13):4963-6]

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Inactivation of Apc perturbs mammary development, but only directly results in acanthoma in the context of Tcf-1 deficiency

Cited by 37 publications

References 54 publications

Cancer genetics: mouse models of intestinal cancer

Cancer genetics: mouse models of intestinal cancer

Targeted expression of HGF/SF in mouse mammary epithelium leads to metastatic adenosquamous carcinomas through the activation of multiple signal transduction pathways

C-Myc Is a Critical Mediator of the Phenotypes of Apc Loss in the Intestine

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