title: The transcriptional regulators TAZ and YAP direct transforming growth factor β-induced tumorigenic phenotypes in breast cancer cells.
abstract: Uncontrolled transforming growth factor-β (TGFβ) signaling promotes aggressive metastatic properties in late-stage breast cancers. However, how TGFβ-mediated cues are directed to induce tumorigenic events is poorly understood, particularly given that TGFβ has clear tumor suppressing activity in other contexts. Here, we demonstrate that the transcriptional regulators TAZ and YAP (TAZ/YAP), key effectors of the Hippo pathway, are necessary to promote and maintain TGFβ-induced tumorigenic phenotypes in breast cancer cells. Interactions between TAZ/YAP, TGFβ-activated SMAD2/3, and TEAD transcription factors reveal convergent roles for these factors in the nucleus. Genome-wide expression analyses indicate that TAZ/YAP, TEADs, and TGFβ-induced signals coordinate a specific pro-tumorigenic transcriptional program. Importantly, genes cooperatively regulated by TAZ/YAP, TEAD, and TGFβ, such as the novel targets NEGR1 and UCA1, are necessary for maintaining tumorigenic activity in metastatic breast cancer cells. Nuclear TAZ/YAP also cooperate with TGFβ signaling to promote phenotypic and transcriptional changes in nontumorigenic cells to overcome TGFβ-repressive effects. Our work thus identifies cross-talk between nuclear TAZ/YAP and TGFβ signaling in breast cancer cells, revealing novel insight into late-stage disease-driving mechanisms.
authors.affiliation: From the Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts 02118.
authors.forename: Samantha E
authors.initials: SE
authors.lastname: Hiemer
authors.forename: Aleksander D
authors.initials: AD
authors.lastname: Szymaniak
authors.forename: Xaralabos
authors.initials: X
authors.lastname: Varelas
mesh_terms: D000217:Acyltransferases; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015816:Cell Adhesion Molecules, Neuronal; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D005260:Female; D058851:GPI-Linked Proteins; D055106:Genome-Wide Association Study; D006801:Humans; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D062085:RNA, Long Noncoding / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051899:Smad2 Protein / Q000235:genetics / Q000378:metabolism; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*
chemical_list: D015816:Cell Adhesion Molecules, Neuronal; D018797:Cell Cycle Proteins; D058851:GPI-Linked Proteins; C485559:NEGR1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D062085:RNA, Long Noncoding; D012334:RNA, Neoplasm; C497782:SMAD2 protein, human; C497790:SMAD3 protein, human; D051899:Smad2 Protein; D051900:Smad3 Protein; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; C515159:UCA1 RNA, human; C456659:YY1AP1 protein, human; D000217:Acyltransferases; C108675:TAFAZZIN protein, human
keywords: Breast Cancer; Cell Migration; Cell Signaling; Coregulator Transcription; Hippo Pathway; Signal Transduction; Signaling Cross-talk; Transforming Growth Factor β (TGFβ); YAP/TAZ