title: Nuclear repartitioning of galectin-1 by an extracellular glycan switch regulates mammary morphogenesis.
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.
authors: Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA, 94720; ramray@mrdg.iisc.ernet.in bertozzi@stanford.edu mjbissell@lbl.gov.
authors: Ramray
authors: R
authors: Bhat
authors: Department of Chemistry, University of California, Berkeley, CA 94720;
authors: Brian
authors: B
authors: Belardi
authors: Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA, 94720; Department of Pathology, Center for Comparative Medicine, University of California, Davis, CA, 95616;
authors: Hidetoshi
authors: H
authors: Mori
authors: Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, 94305;
authors: Peiwen
authors: P
authors: Kuo
authors: Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA, 94720;
authors: Andrew
authors: A
authors: Tam
authors: Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA, 94720;
authors: William C
authors: WC
authors: Hines
authors: Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, 94305;
authors: Quynh-Thu
authors: QT
authors: Le
authors: Department of Chemistry, Stanford University, Stanford, CA 94305-4401; Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305-4401 ramray@mrdg.iisc.ernet.in bertozzi@stanford.edu mjbissell@lbl.gov.
authors: Carolyn R
authors: CR
authors: Bertozzi
authors: Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA, 94720; ramray@mrdg.iisc.ernet.in bertozzi@stanford.edu mjbissell@lbl.gov.
authors: Mina J
authors: MJ
authors: Bissell
mesh_terms: D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism*; D005260:Female; D037483:Galectin 1 / Q000502:physiology*; D006031:Glycosylation; D008321:Mammary Glands, Animal / Q000254:growth & development*; D015674:Mammary Neoplasms, Animal / Q000209:etiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009024:Morphogenesis; D011134:Polysaccharides / Q000502:physiology*
chemical_list: D037483:Galectin 1; D011134:Polysaccharides
keywords: breast cancer; galectin-1; glycobiology; mammary gland; sialic acid