title: Role of TGF-β receptor III localization in polarity and breast cancer progression.
abstract: The majority of breast cancers originate from the highly polarized luminal epithelial cells lining the breast ducts. However, cell polarity is often lost during breast cancer progression. The type III transforming growth factor-β cell surface receptor (TβRIII) functions as a suppressor of breast cancer progression and also regulates the process of epithelial-to-mesenchymal transition (EMT), a consequence of which is the loss of cell polarity. Many cell surface proteins exhibit polarized expression, being targeted specifically to the apical or basolateral domains. Here we demonstrate that TβRIII is basolaterally localized in polarized breast epithelial cells and that disruption of the basolateral targeting of TβRIII through a single amino acid mutation of proline 826 in the cytosolic domain results in global loss of cell polarity through enhanced EMT. In addition, the mistargeting of TβRIII results in enhanced proliferation, migration, and invasion in vitro and enhanced tumor formation and invasion in an in vivo mouse model of breast carcinoma. These results suggest that proper localization of TβRIII is critical for maintenance of epithelial cell polarity and phenotype and expand the mechanisms by which TβRIII prevents breast cancer initiation and progression.
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, NC 27710.
authors.forename: Alison E
authors.initials: AE
authors.lastname: Meyer
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, NC 27710.
authors.forename: Catherine E
authors.initials: CE
authors.lastname: Gatza
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, NC 27710.
authors.forename: Tam
authors.initials: T
authors.lastname: How
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, NC 27710.
authors.forename: Mark
authors.initials: M
authors.lastname: Starr
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, NC 27710.
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Nixon
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, NC 27710 gerard.blobe@duke.edu.
authors.forename: Gerard C
authors.initials: GC
authors.lastname: Blobe
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D016764:Cell Polarity; D049109:Cell Proliferation; D018450:Disease Progression; D004847:Epithelial Cells / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D006801:Humans; D008819:Mice, Nude; D020125:Mutation, Missense; D009368:Neoplasm Transplantation; D021381:Protein Transport; D011509:Proteoglycans / Q000235:genetics / Q000378:metabolism*; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000502:physiology
chemical_list: D011509:Proteoglycans; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; C071736:betaglycan