LEFTY1 Is a Dual-SMAD Inhibitor that Promotes Mammary Progenitor Growth and Tumorigenesis

Maider Zabala, Neethan A. Lobo, Jane Antony, Luuk S. Heitink, Gunsagar S. Gulati, Jessica Lam, Natesh Parashurama, Kassandra Sanchez, Maddalena Adorno, Shaheen S. Sikandar, Angera H. Kuo, Dalong Qian, Tomer Kalisky, Sopheak Sim, Linus Li, Frederick M. Dirbas, George Somlo, Aaron Newman, Stephen R. Quake, Michael F. Clarke

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

SMAD pathways govern epithelial proliferation, and transforming growth factor β (TGF-β and BMP signaling through SMAD members has distinct effects on mammary development and homeostasis. Here, we show that LEFTY1, a secreted inhibitor of NODAL/SMAD2 signaling, is produced by mammary progenitor cells and, concomitantly, suppresses SMAD2 and SMAD5 signaling to promote long-term proliferation of normal and malignant mammary epithelial cells. In contrast, BMP7, a NODAL antagonist with context-dependent functions, is produced by basal cells and restrains progenitor cell proliferation. In normal mouse epithelium, LEFTY1 expression in a subset of luminal cells and rare basal cells opposes BMP7 to promote ductal branching. LEFTY1 binds BMPR2 to suppress BMP7-induced activation of SMAD5, and this LEFTY1-BMPR2 interaction is specific to tumor-initiating cells in triple-negative breast cancer xenografts that rely on LEFTY1 for growth. These results suggest that LEFTY1 is an endogenous dual-SMAD inhibitor and that suppressing its function may represent a therapeutic vulnerability in breast cancer.

Original languageEnglish
Pages (from-to)284-299.e8
JournalCell Stem Cell
Volume27
Issue number2
DOIs
StatePublished - 6 Aug 2020
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2020

Keywords

  • BMP7
  • BMPR2
  • Lefty1
  • SMAD2
  • SMAD5
  • breast
  • cancer
  • dual-SMAD
  • mammary
  • stem

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