title: Mammary epithelial cell polarity is regulated differentially by p73 isoforms via epithelial-to-mesenchymal transition.
abstract: p73 is expressed as TA and ΔN isoforms, both of which are implicated in tumor suppression and/or promotion. To address how p73 possesses these opposing functions, we developed three-dimensional culture of MCF10A cells, which undergo cell morphogenesis to form polarized spheroids with hollow lumen similar to normal mammary acini in vivo. Here, we showed that upon knockdown of p73, particularly TAp73 but not ΔNp73, MCF10A cells formed irregular and near-normal acini without hollow lumen in three-dimensional culture. We also found that upon knockdown of p73 or TAp73, but not ΔNp73, MCF10A cells underwent epithelial-to-mesenchymal transition (EMT) via down-regulation of E-cadherin coupled with up-regulation of β-catenin and laminin V. In addition, we found that Snail-1, Slug, and Twist, all of which are known to act as EMT inducers by repressing E-cadherin expression, were increased markedly upon knockdown of p73 and TAp73 but little if any by ΔNp73. Furthermore, we showed that knockdown of p73 or TAp73 in MCF10A cells led to a marked increase in cell proliferation and migration. Together, our data suggest that TAp73 is necessary for maintaining normal cell polarity by suppressing EMT.
authors.affiliation: Comparative Oncology Laboratory, Schools of Medicine and Veterinary Medicine, University of California, Davis, California 95616.
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Comparative Oncology Laboratory, Schools of Medicine and Veterinary Medicine, University of California, Davis, California 95616.
authors.forename: Wensheng
authors.initials: W
authors.lastname: Yan
authors.affiliation: Comparative Oncology Laboratory, Schools of Medicine and Veterinary Medicine, University of California, Davis, California 95616.
authors.forename: Yong Sam
authors.initials: YS
authors.lastname: Jung
authors.affiliation: Comparative Oncology Laboratory, Schools of Medicine and Veterinary Medicine, University of California, Davis, California 95616. Electronic address: xbchen@ucdavis.edu.
authors.forename: Xinbin
authors.initials: X
authors.lastname: Chen
mesh_terms: D015820:Cadherins / Q000096:biosynthesis / Q000235:genetics; D015815:Cell Adhesion Molecules / Q000096:biosynthesis / Q000235:genetics; D002461:Cell Line, Transformed; D016764:Cell Polarity / Q000502:physiology*; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation / Q000502:physiology; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D042361:Mammary Glands, Human / Q000166:cytology / Q000378:metabolism*; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D000071250:Snail Family Transcription Factors; D018874:Spheroids, Cellular / Q000166:cytology / Q000378:metabolism; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D051879:Twist-Related Protein 1 / Q000096:biosynthesis / Q000235:genetics; D015854:Up-Regulation / Q000502:physiology; D051176:beta Catenin / Q000096:biosynthesis / Q000235:genetics; D000097794:Kalinin
chemical_list: D015820:Cadherins; D015815:Cell Adhesion Molecules; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; D051879:Twist-Related Protein 1; D051176:beta Catenin; D000097794:Kalinin; C000604407:SNAI1 protein, human; C000606460:TP73 protein, human; C103173:TWIST1 protein, human; C000606369:delta Np73 protein, human