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

15 Citations (Scopus)

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

Fingerprint

Galectin 1
Morphogenesis
Polysaccharides
Breast
Epithelium
Human Mammary Glands
Galectin 2
Protein Transport
Stromal Cells
Glycosylation
Lectins
Extracellular Matrix
Epitopes
Cell Culture Techniques
Epithelial Cells
Ligands
Phenotype

Keywords

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

ASJC Scopus subject areas

  • General

Cite this

Nuclear repartitioning of galectin-1 by an extracellular glycan switch regulates mammary morphogenesis. / Bhat, Ramray; Belardi, Brian; Mori, Hidetoshi; Kuo, Peiwen; Tam, Andrew; Hines, William C.; Le, Quynh Thu; Bertozzi, Carolyn R.; Bissell, Mina J.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 113, No. 33, 16.08.2016, p. E4820-E4827.

Research output: Contribution to journalArticle

Bhat, Ramray ; Belardi, Brian ; Mori, Hidetoshi ; Kuo, Peiwen ; Tam, Andrew ; Hines, William C. ; Le, Quynh Thu ; Bertozzi, Carolyn R. ; Bissell, Mina J. / Nuclear repartitioning of galectin-1 by an extracellular glycan switch regulates mammary morphogenesis. In: Proceedings of the National Academy of Sciences of the United States of America. 2016 ; Vol. 113, No. 33. pp. E4820-E4827.
@article{e6e26b7777494d11a714c6a3b6fa0afd,
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.",
keywords = "Breast cancer, Galectin-1, Glycobiology, Mammary gland, Sialic acid",
author = "Ramray Bhat and Brian Belardi and Hidetoshi Mori and Peiwen Kuo and Andrew Tam and Hines, {William C.} and Le, {Quynh Thu} and Bertozzi, {Carolyn R.} and Bissell, {Mina J.}",
year = "2016",
month = "8",
day = "16",
doi = "10.1073/pnas.1609135113",
language = "English (US)",
volume = "113",
pages = "E4820--E4827",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "33",

}

TY - JOUR

T1 - Nuclear repartitioning of galectin-1 by an extracellular glycan switch regulates mammary morphogenesis

AU - Bhat, Ramray

AU - Belardi, Brian

AU - Mori, Hidetoshi

AU - Kuo, Peiwen

AU - Tam, Andrew

AU - Hines, William C.

AU - Le, Quynh Thu

AU - Bertozzi, Carolyn R.

AU - Bissell, Mina J.

PY - 2016/8/16

Y1 - 2016/8/16

N2 - 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.

AB - 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.

KW - Breast cancer

KW - Galectin-1

KW - Glycobiology

KW - Mammary gland

KW - Sialic acid

UR - http://www.scopus.com/inward/record.url?scp=84982105738&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84982105738&partnerID=8YFLogxK

U2 - 10.1073/pnas.1609135113

DO - 10.1073/pnas.1609135113

M3 - Article

C2 - 27496330

AN - SCOPUS:84982105738

VL - 113

SP - E4820-E4827

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 33

ER -