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Letter
Nature Genetics  35, 252 - 257 (2003)
Published online: 28 September 2003; | doi:10.1038/ng1249

Loss of collagenase-2 confers increased skin tumor susceptibility to male mice

Milagros Balbín1, Antonio Fueyo2, Angus M Tester3, Alberto M Pendás1, Ana S Pitiot1, Aurora Astudillo4, Christopher M Overall3, Steven D Shapiro5 & Carlos López-Otín1

1  Departamentos de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología, Universidad de Oviedo, 33006-Oviedo, Spain.

2  Departamentos de Biología Funcional, Facultad de Medicina, Instituto Universitario de Oncología, Universidad de Oviedo, 33006-Oviedo, Spain.

3  Departments of Biochemistry and Molecular Biology and Oral Biological and Medical Sciences, C.I.H.R. Group in Matrix Dynamics, University of British Columbia, Vancouver B.C., V6T 1Z3 Canada.

4  Servicio de Anatomía Patológica, Hospital Central de Asturias, 33006-Oviedo, Spain.

5  Department of Medicine, Pulmonary and Critical Care, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.

Correspondence should be addressed to Carlos López-Otín CLO@correo.uniovi.es
Matrix metalloproteinases (MMPs) have fundamental roles in tumor progression1, 2, but most clinical trials with MMP inhibitors have not shown improvements in individuals with cancer3. This may be partly because broad-range inhibitors also reduce host-protective antitumor properties of individual MMPs. We generated mice deficient in collagenase-2 (Mmp8), an MMP mainly produced by neutrophils in inflammatory reactions and detected in some malignant tumors1, 4. Loss of Mmp8 did not cause abnormalities during embryonic development or in adult mice. Contrary to previous studies with MMP-deficient mice, however, the absence of Mmp8 strongly increased the incidence of skin tumors in male Mmp8-/-mice. Female Mmp8-/-mice whose ovaries were removed or were treated with tamoxifen were also more susceptible to tumors compared with wild-type mice. Bone marrow transplantation experiments confirmed that Mmp8 supplied by neutrophils was sufficient to restore the natural protection against tumor development mediated by this protease in male mice. Histopathological analysis showed that mutant mice had abnormalities in the inflammatory response induced by carcinogens. Our study identifies a paradoxical protective role for Mmp8 in cancer and provides a genetic model to evaluate the molecular basis of gender differences in cancer susceptibility.


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Nature Genetics
ISSN: 1061-4036
EISSN: 1546-1718
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