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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 113; no. 33; pp. E4820 - E4827
• Main Authors: Bhat, Ramray, Belardi, Brian, Mori, Hidetoshi, Kuo, Peiwen, Tam, Andrew, Hines, William C., Le, Quynh-Thu, Bertozzi, Carolyn R., Bissell, Mina J.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 16-08-2016
• Series: From the Cover
• Subjects: Animals; Biological Sciences; Buds; Cell adhesion & migration; Cell Nucleus - metabolism; Cells; Female; Galectin 1 - physiology; Genotype & phenotype; Glycosylation; Mammary Glands, Animal - growth & development; Mammary Neoplasms, Animal - etiology; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Morphogenesis; PNAS Plus; Polysaccharides - physiology; Tissues; Translocation; breast cancer; mammary gland; sialic acid; glycobiology; galectin-1
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1609135113

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.