Direct interaction between NHERF1 and Frizzled regulates β-catenin signaling

Oncogene. 2011 Jan 6;30(1):32-42. doi: 10.1038/onc.2010.389. Epub 2010 Aug 30.


Although Wnt-Frizzled (Fzd) signaling is critical in the pathophysiology of carcinomas, its role in human breast cancer has been difficult to establish. We show here that the adaptor protein Na(+)/H(+) exchange regulatory factor1 (NHERF1), a protein abundantly expressed in normal mammary epithelium, regulates Wnt signaling, maintaining low levels of β-catenin activation. NHERF1's effects are mediated by direct interactions between one of its PSD-95/drosophila discs large/ZO-1 (PDZ) domains and the C-terminus of a subset of Fzd receptors. Loss of NHERF1 in breast cancer cell lines enhances canonical Wnt signaling and Wnt-dependent cell proliferation. Furthermore, the mammary glands of NHERF1-knockout mice exhibit increased mammary duct density accompanied by increased proliferation and β-catenin activity. Finally, we demonstrate a negative correlation between NHERF1 expression and nuclear β-catenin in human breast carcinomas. Taken together, these results provide a novel insight into the regulation of Wnt signaling in normal and neoplastic breast tissues, and identify NHERF1 as an important regulator of the pathogenesis of breast tumors.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Cell Proliferation
  • Cricetinae
  • Cricetulus
  • Female
  • Frizzled Receptors / genetics
  • Frizzled Receptors / metabolism*
  • Humans
  • Mice
  • Mice, Knockout
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism*
  • Signal Transduction
  • Sodium-Hydrogen Exchangers / genetics
  • Sodium-Hydrogen Exchangers / metabolism*
  • beta Catenin / genetics
  • beta Catenin / metabolism*


  • Frizzled Receptors
  • Phosphoproteins
  • Sodium-Hydrogen Exchangers
  • beta Catenin
  • sodium-hydrogen exchanger regulatory factor