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Mammalian Genome

, Volume 27, Issue 11–12, pp 556–564 | Cite as

Deregulation of the Hippo pathway in mouse mammary stem cells promotes mammary tumorigenesis

  • Hongbin Li
  • Barry M. GumbinerEmail author
Article

Abstract

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.

Keywords

Mammary Gland Mammary Tumor Mammary Gland Development Mammary Tumorigenesis Mammary Stem Cell 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

We wish to thank Yongliang Huo for teaching us the MaSC transplantation method while at UVA. We also thank Nam Gyun Kim and Alisha Mendonsa for reading drafts of the manuscript and providing feedback. The work in this manuscript was supported by NIH Grant R01 GM098615 to BMG.

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Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  1. 1.Department of Cell BiologyUniversity of Virginia School of MedicineCharlottesvilleUSA
  2. 2.Department of Pediatrics, Center for Developmental Biology and Regenerative Medicine, Seattle Children’s Research InstituteUniversity of Washington School of MedicineSeattleUSA

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