Nuclear repartitioning of galectin-1 by an extracellular glycan switch regulates mammary morphogenesis

Ramray Bhat, Brian Belardi, Hidetoshi Mori, Peiwen Kuo, Andrew Tam, William C. Hines, Quynh Thu Le, Carolyn R. Bertozzi, Mina J. Bissell

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

Branching morphogenesis in the mammary gland is achieved by the migration of epithelial cells through a microenvironment consisting of stromal cells and extracellular matrix (ECM). Here we show that galectin-1 (Gal-1), an endogenous lectin that recognizes glycans bearing N- Acetyllactosamine (LacNAc) epitopes, induces branching migration of mammary epithelia in vivo, ex vivo, and in 3D organotypic cultures. Surprisingly, Gal-1's effects on mammary patterning were independent of its glycan-binding ability and instead required localization within the nuclei of mammary epithelia. Nuclear translocation of Gal-1, in turn, was regulated by discrete cell-surface glycans restricted to the front of the mammary end buds. Specifically, α2,6-sialylation of terminal LacNAc residues in the end buds masked Gal-1 ligands, thereby liberating the protein for nuclear translocation. Within mammary epithelia, Gal-1 localized within nuclear Gemini bodies and drove epithelial invasiveness. Conversely, unsialylated LacNAc glycans, enriched in the epithelial ducts, sequestered Gal-1 in the extracellular environment, ultimately attenuating invasive potential. We also found that malignant breast cells possess higher levels of nuclear Gal-1 and α2,6- SA and lower levels of LacNAc than nonmalignant cells in culture and in vivo and that nuclear localization of Gal-1 promotes a transformed phenotype. Our findings suggest that differential glycosylation at the level of tissue microanatomy regulates the nuclear function of Gal-1 in the context of mammary gland morphogenesis and in cancer progression.

Original languageEnglish (US)
Pages (from-to)E4820-E4827
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number33
DOIs
StatePublished - Aug 16 2016
Externally publishedYes

Keywords

  • Breast cancer
  • Galectin-1
  • Glycobiology
  • Mammary gland
  • Sialic acid

ASJC Scopus subject areas

  • General

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