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A tissue reconstitution model to study cancer cell-intrinsic and -extrinsic factors in mammary tumourigenesis

Evers, Bastiaan, Speksnijder, Ewoud N., Schut, Eva, Ciampricotti, Metamia, Smalley, Matthew John, Derksen, Patrick W. B., Jonkers, Jos and de Visser, Karin E. 2010. A tissue reconstitution model to study cancer cell-intrinsic and -extrinsic factors in mammary tumourigenesis. Journal of Pathology 220 (1) , pp. 34-44. 10.1002/path.2655

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Abstract

The contribution of cancer cell-intrinsic and -extrinsic factors to metastatic breast cancer is still poorly understood, hampering development of novel therapeutic strategies that decrease breast cancer mortality. Cre/loxP-based conditional mouse models of breast cancer present unique opportunities to study sporadic tumour formation and progression in a controlled setting. Unfortunately, the generation of mouse strains carrying multiple mutant alleles needed for such studies is very time-consuming. Moreover, conditional mouse tumour models do not permit independent manipulation of tumour cell-intrinsic and -extrinsic factors. Although the latter can be achieved by cleared fat-pad transplantation of mouse mammary epithelial cells (MMECs) from tumour suppressor gene (TSG) knockouts into wild-type or mutant recipients, this procedure is not possible for mutations that cause embryonic lethality or preclude mammary gland development. Here we show that cleared fat-pad transplantations with MMECs isolated from K14cre;Cdh1F/F; Trp53F/F mice expressing Cre recombinase under control of the cytokeratin-14 promoter and carrying conditional null alleles for p53 and E-cadherin (Cdh1) first resulted in the formation of phenotypically normal mammary glands, followed by the development of invasive metastatic mammary tumours. Tumour formation in the recipients mimicked tumour latency, spectrum, morphology, immunophenotype, and metastatic characteristics of the original mammary tumour model. This transplantation system, which can be expanded to other conditional TSG knockouts, permits independent genetic analysis of stromal factors and testing of additional cancer cell-intrinsic mutations that would otherwise be embryonic lethal or require intensive breeding. Copyright © 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
Subjects: Q Science > Q Science (General)
R Medicine > RB Pathology
Uncontrolled Keywords: breast cancer; conditional mouse model; mammary gland reconstitution; metastasis; stroma; invasive lobular carcinoma
Publisher: Wiley
ISSN: 0022-3417
Funders: Netherlands Organization for Scientific Research (NWO) [Vidi 917.36.348]; Dutch Cancer Society [NKI 2006-3486, NKI 2006-3715]; NWO [Vidi 917.96.307, Veni 916.56.135, Vidi 016.096.318]; EMBO [ALTF 325-2001]; Breakthrough Breast Cancer ; NHS
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Last Modified: 24 Apr 2019 12:20
URI: http://orca.cf.ac.uk/id/eprint/18217

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