title: The Notch pathway inhibits TGFβ signaling in breast cancer through HEYL-mediated crosstalk.
abstract: Acquired resistance to TGFβ is a key step in the early stages of tumorigenesis. Mutations in TGFβ signaling components are rare, and little is known about the development of resistance in breast cancer. On the other hand, an activated Notch pathway is known to play a substantial role in promoting breast cancer development. Here, we present evidence of crosstalk between these two pathways through HEYL. HEYL, a basic helix-loop-helix transcription factor and a direct target of Notch signaling, is specifically overexpressed in breast cancer. HEYL represses TGFβ activity by binding to TGFβ-activated Smads. HeyL(-/-) mice have defective mammary gland development with fewer terminal end buds. On the other hand, HeyL transgenic mice show accelerated mammary gland epithelial proliferation and 24% of multiparous mice develop mammary gland cancer. Therefore, repression of TGFβ signaling by Notch acting through HEYL may promote initiation of breast cancer.
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Liangfeng
authors.initials: L
authors.lastname: Han
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Adam
authors.initials: A
authors.lastname: Diehl
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Nguyen K
authors.initials: NK
authors.lastname: Nguyen
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Preethi
authors.initials: P
authors.lastname: Korangath
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Weiwen
authors.initials: W
authors.lastname: Teo
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Soonweng
authors.initials: S
authors.lastname: Cho
authors.affiliation: Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Scott
authors.initials: S
authors.lastname: Kominsky
authors.affiliation: Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: David L
authors.initials: DL
authors.lastname: Huso
authors.affiliation: Laboratory Animal Science Program, Science Applications International Corporation, Frederick, Maryland.
authors.forename: Lionel
authors.initials: L
authors.lastname: Feigenbaum
authors.affiliation: HIV Drug Resistance Program, National Cancer Institute, Frederick, Maryland.
authors.forename: Alan
authors.initials: A
authors.lastname: Rein
authors.affiliation: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Pedram
authors.initials: P
authors.lastname: Argani
authors.affiliation: Breakthrough Breast Cancer Unit, School of Cancer, University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom.
authors.forename: Goran
authors.initials: G
authors.lastname: Landberg
authors.affiliation: Developmental Biochemistry, Comprehensive Cancer Center Mainfraken and Theodor-Boveri-Institute, Biocenter, University of Wuerzburg, Wuerzburg, Germany.
authors.forename: Manfred
authors.initials: M
authors.lastname: Gessler
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland. saras@jhmi.edu.
authors.forename: Saraswati
authors.initials: S
authors.lastname: Sukumar
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000502:physiology*; D001943:Breast Neoplasms / Q000473:pathology*; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D051880:Receptors, Notch / Q000502:physiology*; D012097:Repressor Proteins / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D051900:Smad3 Protein / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051880:Receptors, Notch; D012097:Repressor Proteins; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; C497364:HEYL protein, human; C497790:SMAD3 protein, human