Deregulation of the Hippo pathway in mouse mammary stem cells promotes mammary tumorigenesis.
The Hippo-YAP pathway mediates organ size control, contact inhibition, and tumorigenesis. It is a kinase cascade that inhibits the nuclear localization and transcriptional activities of YAP and TAZ. E-cadherin, cell junctions, polarity proteins, and the merlin/NF2 tumor suppressor activate the pathway to inhibit YAP/TAZ activity, while growth factor signaling inhibits the pathway to activate YAP/TAZ in the nucleus. We examined its role in the development of mouse mammary glands and tumor formation using gland reconstitution by transplantation of genetically modified mammary stem cells (MaSCs). Knockdown of YAP and TAZ with shRNA in MaSCs did not inhibit gland reconstitution. In contrast, knockdown of β-catenin blocked gland reconstitution, consistent with the known role of Wnt signaling in mammary gland development. However, we find that Hippo signaling is involved in mammary tumor formation. Expression of a constitutively active form of YAP caused rapid formation of large tumors. Moreover, knockdown of YAP/TAZ slowed the development of tumors in polyoma middle T transgenic mice, a well-studied mammary tumor model involving activation of several signaling pathways. YAP accumulated in nuclei of mammary glands in ErbB2/EGFR-transgenic mice, suggesting that EGFR signaling affects YAP in vivo similar to cell culture. ErbB2/EGFR-transgenic mice develop mammary tumors in 7-8 months, but surprisingly, MaSCs from these mice did not form tumors when transplanted into host mice. Nonetheless, expression of dominant-negative Lats, which inhibits Hippo signaling, leads to tumor formation in ErbB2-transgenic mice, suggesting that Hippo signaling is involved in EGFR-induced mammary tumorigenesis.
Department of Cell Biology, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA.
Hongbin
H
Li
Department of Cell Biology, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA. gumbiner@uw.edu.|Department of Pediatrics, Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, University of Washington School of Medicine, 1900 9th Ave. Mailstop JMB-5, Seattle, WA, 98101, USA. gumbiner@uw.edu.
Barry M
BM
Gumbiner
D000217:Acyltransferases; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D063646:Carcinogenesis / Q000235:genetics*; D018797:Cell Cycle Proteins; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D000090683:Hippo Signaling Pathway; D006801:Humans; D008321:Mammary Glands, Animal / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D010750:Phosphoproteins / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics; D060449:Wnt Signaling Pathway / Q000235:genetics; D000091102:YAP-Signaling Proteins; D051176:beta Catenin / Q000235:genetics
D000217:Acyltransferases; D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D066246:ErbB Receptors; D010750:Phosphoproteins; D017346:Protein Serine-Threonine Kinases; D034741:RNA, Small Interfering; D018719:Erb-b2 Receptor Tyrosine Kinases; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; D051176:beta Catenin; C486223:Yap1 protein, mouse; C486363:tafazzin protein, mouse; C490501:Lats1 protein, mouse; C541485:EGFR protein, mouse; C524056:Erbb2 protein, mouse