CRIPTO/GRP78 signaling maintains fetal and adult mammary stem cells ex vivo

Stem Cell Reports. 2014 Apr 3;2(4):427-39. doi: 10.1016/j.stemcr.2014.02.010. eCollection 2014 Apr 8.


Little is known about the extracellular signaling factors that govern mammary stem cell behavior. Here, we identify CRIPTO and its cell-surface receptor GRP78 as regulators of stem cell behavior in isolated fetal and adult mammary epithelial cells. We develop a CRIPTO antagonist that promotes differentiation and reduces self-renewal of mammary stem cell-enriched populations cultured ex vivo. By contrast, CRIPTO treatment maintains the stem cell phenotype in these cultures and yields colonies with enhanced mammary gland reconstitution capacity. Surface expression of GRP78 marks CRIPTO-responsive, stem cell-enriched fetal and adult mammary epithelial cells, and deletion of GRP78 from adult mammary epithelial cells blocks their mammary gland reconstitution potential. Together, these findings identify the CRIPTO/GRP78 pathway as a developmentally conserved regulator of fetal and adult mammary stem cell behavior ex vivo, with implications for the stem-like cells found in many cancers.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activin Receptors, Type I / genetics
  • Activin Receptors, Type I / metabolism
  • Adult Stem Cells / cytology
  • Adult Stem Cells / metabolism
  • Biomarkers
  • Cell Differentiation
  • Cell Line
  • Cell Membrane / metabolism
  • Cells, Cultured
  • Endoplasmic Reticulum Chaperone BiP
  • Epithelial Cells / cytology
  • Epithelial Cells / metabolism
  • GPI-Linked Proteins / antagonists & inhibitors
  • GPI-Linked Proteins / genetics
  • GPI-Linked Proteins / metabolism*
  • Gene Expression
  • Heat-Shock Proteins / genetics
  • Heat-Shock Proteins / metabolism*
  • Humans
  • Intercellular Signaling Peptides and Proteins / genetics
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Mammary Glands, Human / cytology*
  • Mammary Glands, Human / physiology
  • Mutation
  • Neoplasm Proteins / antagonists & inhibitors
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Protein Binding
  • Regeneration
  • Signal Transduction*
  • Stem Cells / cytology
  • Stem Cells / metabolism*


  • Biomarkers
  • Endoplasmic Reticulum Chaperone BiP
  • GPI-Linked Proteins
  • HSPA5 protein, human
  • Heat-Shock Proteins
  • Intercellular Signaling Peptides and Proteins
  • Neoplasm Proteins
  • TDGF1 protein, human
  • ACVR1B protein, human
  • Activin Receptors, Type I