4.8 Article

Role of the polarity determinant crumbs in suppressing mammalian epithelial tumor progression

Journal

CANCER RESEARCH
Volume 68, Issue 11, Pages 4105-4115

Publisher

AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-07-6814

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Funding

  1. Howard Hughes Medical Institute Funding Source: Medline
  2. NCI NIH HHS [R37 CA053370, R37CA53370, L30 CA116898, L30 CA116898-02, R37 CA053370-18] Funding Source: Medline

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Most tumors are epithelial-derived, and although disruption of polarity and aberrant cellular junction formation is a poor prognosticator in human cancer, the role of polarity determinants in oncogenesis is poorly understood. Using in vivo selection, we identified a mammalian orthologue of the Drosophila polarity regulator crumbs as a gene whose loss of expression promotes tumor progression. Immortal baby mouse kidney epithelial cells selected in vivo to acquire tumorigenicity displayed dramatic repression of crumbs3 (crb3) expression associated with disruption of tight junction formation, apicobasal polarity, and contact-inhibited growth. Restoration of crb3 expression restored junctions, polarity, and contact inhibition while suppressing migration and metastasis. These findings suggest a role for mammalian polarity determinants in suppressing tumorigenesis that may be analogous to the well-studied polarity tumor suppressor mechanisms in Drosophila.

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