title: Nuclear localization of maspin is essential for its inhibition of tumor growth and metastasis.
abstract: Maspin (mammary serine protease inhibitor or SerpinB5) acts as a tumor suppressor when overexpressed in aggressive cancer cell lines. However, its role in human cancer is controversial. Maspin expression has been associated with a poor prognosis in some studies, whereas in others, with favorable outcome. The clinical data suggest, however, that nuclear-localized maspin is associated with improved survival. We hypothesized that the tumor suppressor activity of maspin may require nuclear localization, and that the discordance between clinical and experimental reports is a consequence of the variable subcellular distribution of maspin. Furthermore, we surmized that nuclear maspin could function as a tumor suppressor through the regulation of genes involved in tumor growth and invasion. Maspin or maspin fused to a nuclear export signal were expressed in metastatic human breast and epidermoid carcinoma cell lines. We found that pan-cellular localized maspin inhibited in vivo tumor growth and metastasis when assessed in xenograft chicken embryo and murine mammary fat pad injection models. However, when maspin was excluded from the nucleus via a nuclear exclusion signal, it no longer functioned as a metastasis suppressor. Using chromatin immunoprecipitation, we show that nuclear maspin was enriched at the promoter of colony-stimulating factor-1 (CSF-1) and associated with diminished levels of CSF-1 mRNA. Our findings demonstrate that the nuclear localization of maspin is required for its tumor and metastasis suppressor functions in vivo, and suggest that its mechanism of action involves, in part, direct association of maspin with target genes.
authors.affiliation: London Regional Cancer Program, London, Ontario, Canada.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Goulet
authors.forename: Wendy
authors.initials: W
authors.lastname: Kennette
authors.forename: Amber
authors.initials: A
authors.lastname: Ablack
authors.forename: Carl O
authors.initials: CO
authors.lastname: Postenka
authors.forename: M Nicole
authors.initials: MN
authors.lastname: Hague
authors.forename: Joe S
authors.initials: JS
authors.lastname: Mymryk
authors.forename: Alan B
authors.initials: AB
authors.lastname: Tuck
authors.forename: Vincent
authors.initials: V
authors.lastname: Giguère
authors.forename: Ann F
authors.initials: AF
authors.lastname: Chambers
authors.forename: John D
authors.initials: JD
authors.lastname: Lewis
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000378:metabolism; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D002843:Chromatin / Q000378:metabolism; D005260:Female; D006801:Humans; D016173:Macrophage Colony-Stimulating Factor / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D011401:Promoter Regions, Genetic; D015843:Serpins / Q000378:metabolism*
chemical_list: D002843:Chromatin; C085344:SERPIN-B5; D015843:Serpins; D016173:Macrophage Colony-Stimulating Factor