The Hippo Signaling Transducer TAZ Regulates Mammary Gland Morphogenesis and Carcinogen-induced Mammary Tumorigenesis

Kayla E Denson; Ashley L Mussell; He Shen; Alexander Truskinovsky; Nuo Yang; Natesh Parashurama; Yanmin Chen; Costa Frangou; Fajun Yang; Jianmin Zhang

doi:10.1038/s41598-018-24712-5

The Hippo Signaling Transducer TAZ Regulates Mammary Gland Morphogenesis and Carcinogen-induced Mammary Tumorigenesis

Sci Rep. 2018 Apr 24;8(1):6449. doi: 10.1038/s41598-018-24712-5.

Authors

Affiliations

¹ Department of Cancer Genetics & Genomics, Roswell Park Cancer Institute, Buffalo, NY, 14263, USA.
² Department of Pathology, Roswell Park Cancer Institute, Buffalo, NY, 14263, USA.
³ Department of Anesthesiology, University at Buffalo, The State University of New York, NY, 14214, USA.
⁴ Department of Chemical & Biological Engineering, University at Buffalo, The State University of New York, NY, 14214, USA.
⁵ Harvard TH Chan School of Public Health, Molecular and Integrative Physiological Sciences, 665 Huntington Avenue, Boston, MA, 02115, USA.
⁶ Departments of Medicine, Diabetes Research Center, Albert Einstein College of Medicine, Bronx, NY, 10461, USA.
⁷ Department of Cancer Genetics & Genomics, Roswell Park Cancer Institute, Buffalo, NY, 14263, USA. [email protected].

Abstract

Hippo signaling pathway is an evolutionarily conserved pathway that controls organ size by regulating cell proliferation, apoptosis and stem cell self-renewal. TAZ (transcriptional coactivator with the PDZ-binding motif) is a key downstream effector of the mammalian Hippo pathway. Here, using a transgenic mouse model with mammary-gland-specific expression of constitutively active TAZ, we found that TAZ induction in mammary epithelial cells was associated with an increase in mammary glandular size, which probably resulted from adipocyte hypertrophy. Consistent with its known oncogenic potential, we observed tumor formation in TAZ transgenic mice after administration of the carcinogen 7,12-dimethylbenzanthracene (DMBA) and demonstrated that tumorigenesis was reliant on the presence of TAZ. Our findings establish a previously unknown roles of TAZ in regulating both mammary gland morphogenesis as well as carcinogen-induced mammary tumor formation.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing / metabolism
Adaptor Proteins, Signal Transducing / physiology
Animals
Apoptosis
Carcinogenesis / metabolism
Cell Proliferation
Cell Transformation, Neoplastic
Epithelial Cells / metabolism
Female
Hippo Signaling Pathway
Humans
Intracellular Signaling Peptides and Proteins / metabolism*
Intracellular Signaling Peptides and Proteins / physiology*
Mammary Glands, Animal / metabolism*
Mammary Neoplasms, Animal / metabolism
Mice
Mice, Inbred C57BL
Mice, Transgenic
Protein Serine-Threonine Kinases / metabolism
Protein Serine-Threonine Kinases / physiology
Signal Transduction
Trans-Activators
Transcription Factors / metabolism
Transcriptional Coactivator with PDZ-Binding Motif Proteins

Substances

Adaptor Proteins, Signal Transducing
Intracellular Signaling Peptides and Proteins
Trans-Activators
Transcription Factors
Transcriptional Coactivator with PDZ-Binding Motif Proteins
WWTR1 protein, human
Wwtr1 protein, mouse
Protein Serine-Threonine Kinases

Abstract

Publication types

MeSH terms

Substances

Grants and funding