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J. Biol. Chem., Vol. 280, Issue 31, 28731-28741, August 5, 2005

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Immortalized Mouse Mammary Fibroblasts Lacking Dioxin Receptor Have Impaired Tumorigenicity in a Subcutaneous Mouse Xenograft Model^*

Sonia Mulero-Navarro, Eulalia Pozo-Guisado, Pedro A. Pérez-Mancera, Alberto Álvarez-Barrientos¶, Inmaculada Catalina-Fernández||, Emilia Hernández-Nieto||, Javier Sáenz-Santamaria||, Natalia Martínez**, José M. Rojas**, Isidro Sánchez-García, and Pedro M. Fernández-Salguero

From the Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias, Universidad de Extremadura, Avenida de Elvas s/n, 06071 Badajoz, Spain, the Instituto de Biología Molecular y Celular del Cáncer, Centro de Investigacion del Cáncer, CSIC/Universidad de Salamanca, Campus Unamuno, 37007 Salamanca, Spain, the ^¶Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III, 28029 Madrid, Spain, the ^||Hospital Perpetuo Socorro, 06010 Badajoz, Spain, and the ^**Unidad de Biología Celular, Instituto de Salud Carlos III, Centro Nacional de Microbiología, Majadahonda, 28220 Madrid, Spain

Although the dioxin receptor, the aryl hydrocarbon receptor (AhR), is considered a major regulator of xenobiotic-induced carcinogenesis, its role in tumor formation in the absence of xenobiotics is still largely unknown. Trying to address this question, we have produced immortalized cell lines from wild-type (T-FGM-AhR+/+) and mutant (T-FGM-AhR-/-) mouse mammary fibroblasts by stable co-transfection with the simian virus 40 (SV-40) large T antigen and proto-oncogenic c-H-Ras. Both cell lines had a myofibroblast phenotype and similar proliferation, doubling time, SV-40 and c-H-Ras expression and activity, and cell cycle distribution. AhR+/+ and AhR-/- cells were also equally able to support growth factor- and anchorage-independent proliferation. However, the ability of T-FGM-AhR-/- to induce subcutaneous tumors (leimyosarcomas) in NOD/SCID-immunodeficient mice was close to 4-fold lower than T-FGM-AhR+/+. In culture, T-FGM-AhR-/- had diminished migration in collagen-I and decreased lamellipodia formation. VEGFR-1/Flt-1, a VEGF receptor that regulates cell migration and blood vessel formation, was also down-regulated in AhR-/- cells. Signaling through the ERK-FAK-PKB/AKT-Rac-1 pathway, which contributes to cell motility and invasion, was also significantly inhibited in T-FGM-AhR-/-. Thus, the lower tumorigenic potential of T-FGM-AhR-/- could result from a compromised adaptability of these cells to the in vivo microenvironment, possibly because of an impaired ability to migrate and to respond to angiogenesis.

Received for publication, April 26, 2005 , and in revised form, May 20, 2005.

^* This work has been funded by Grant SAF2002-00034 from the Spanish Ministry of Science and Technology and from the Junta de Extremadura (2PR01A092) (to P. M. F.-S.). Work in the I. S. G. laboratory was supported by grants from the MCyT (BIO2000-0453-01, SAF2003-01103, and FIT-010000-2004-157), Junta de Castilla y León (CSI06/13), ADE Castilla y Leon (04/04/SA/0001), FIS (PI020138, G03/179, and G03/136) and the USAL-CIBASA project. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias, Universidad de Extremadura, Avenida de Elvas s/n, 06071-Badajoz, Spain. Tel.: 34-924-289422; Fax: 34-924-289419; E-mail: pmfersal{at}unex.es.

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