Evers, B., Speksnijder, E. N., Schut, E., Ciampricotti, M., Smalley, M. J., Derksen, P. W. B., Jonkers, J., de Visser, K. 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. ISSN 0022-3417

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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;Cdh1(F/F); TrP53(F/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 (C) 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Item Type:	Article
Authors (ICR Faculty only):	Smalley, Matthew
All Authors:	Evers, B., Speksnijder, E. N., Schut, E., Ciampricotti, M., Smalley, M. J., Derksen, P. W. B., Jonkers, J., de Visser, K. E.
Uncontrolled Keywords:	breast cancer; conditional mouse model; mammary gland reconstitution; metastasis; stroma; invasive lobular carcinoma;TUMOR-SUPPRESSOR GENE; BREAST-CANCER; E-CADHERIN; MOUSE MODELS; P53; MICE; MUTATION; ANGIOGENESIS; BRCA2; LEADS
Funding Acknowledgement:	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
Funding Text:	We thank Dr Ligun Luo for kindly providing mTmG mice. This work was supported by grants from the Netherlands Organization for Scientific Research (NWO) (Vidi 917.36.348 to JJ) and the Dutch Cancer Society (NKI 2006-3486 to JJ). KEdV is funded by the Dutch Cancer Society (NKI 2006-3715 to KEdV and, JJ) and the NWO (Vidi 917.96.307 to KEdV), MJS was supported by in EMBO Long-Term Fellowship (ALTF 325-2001) and is Currently funded by Breakthrough Breast Cancer. MJS also acknowledges NHS funding to the NIHR Biomedical Research Centre. PWBD was supported by it grant from the NWO (Veni 916.56.135) and is currently funded by the NWO (Vidi 016.096.318).
Research teams:	Closed research groups > Molecular Pathology ICR divisions > Breast Cancer Research > Gene Function ICR divisions > Molecular Pathology > Gene Function Closed research groups > Mammary Stem Cells
Depositing User:	Users 10 not found.
Date Deposited:	18 Jan 2010 14:46
Last Modified:	25 Feb 2014 15:25
URI:	http://publications.icr.ac.uk/id/eprint/9217

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