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Published on: October 11, 2011
LEFTY1 Is a Dual-SMAD Inhibitor that Promotes Mammary Progenitor Growth and Tumorigenesis
Maider Zabala1, Neethan A Lobo1, Jane Antony1
1Institute for Stem Cell Biology and Regenerative Medicine, School of Medicine, Stanford University, Stanford, CA, USA.
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.
Insights
LEFTY1, a novel inhibitor, promotes mammary epithelial cell proliferation by suppressing SMAD signaling. Targeting LEFTY1 may offer a new therapeutic strategy for breast cancer treatment.
Area of Science:
- Cell Biology
- Developmental Biology
- Cancer Research
Background:
- SMAD pathways regulate epithelial cell proliferation and mammary gland development.
- Transforming growth factor-beta (TGF-β) and bone morphogenetic protein (BMP) signaling pathways have distinct roles in mammary homeostasis.
- NODAL/SMAD2 signaling is crucial in various developmental processes.
Purpose of the Study:
- To investigate the role of LEFTY1 in mammary epithelial cell proliferation and breast cancer.
- To elucidate the interaction between LEFTY1, BMP7, and SMAD signaling in mammary development.
- To identify potential therapeutic targets in triple-negative breast cancer.
Main Methods:
- Analysis of LEFTY1 expression in mammary progenitor cells.
- Investigation of LEFTY1's effect on SMAD2 and SMAD5 signaling.
- Study of BMP7's role as a NODAL antagonist.
- Examination of LEFTY1-BMPR2 interaction in breast cancer xenografts.
Main Results:
- LEFTY1, produced by mammary progenitor cells, suppresses SMAD2 and SMAD5 signaling, promoting epithelial cell proliferation.
- BMP7, produced by basal cells, restrains progenitor cell proliferation and opposes LEFTY1 in normal mammary epithelium.
- LEFTY1 binds BMPR2 to inhibit BMP7-induced SMAD5 activation, a mechanism critical for tumor-initiating cells in triple-negative breast cancer.
- LEFTY1 acts as an endogenous dual-SMAD inhibitor.
Conclusions:
- LEFTY1 promotes long-term proliferation of normal and malignant mammary epithelial cells.
- The interaction between LEFTY1 and BMPR2 is specific to tumor-initiating cells and essential for their growth.
- Inhibition of LEFTY1 function presents a potential therapeutic vulnerability in breast cancer.
