The APC Tumor Suppressor Is Required for Epithelial Integrity in the Mouse Mammary Gland

J Cell Physiol. 2009 Aug;220(2):319-31. doi: 10.1002/jcp.21766.

Abstract

Inactivation of the adenomatous polyposis coli (APC) tumor suppressor has been associated with mammary tumorigenesis in mouse models and through epidemiological studies of human breast cancers, but the normal role for APC in mammary development has not been thoroughly characterized. We report here that Apc(Min/+) mice containing one functional allele of Apc have severely disrupted lobuloalveolar development during pregnancy and lactation, time points at which Apc gene expression is at its highest levels in normal mice. This phenotype was accompanied by altered proliferation during pregnancy and involution, increased apoptosis throughout lactation, the formation of preneoplastic lesions and changes in specific genes associated with each of these processes. Neither modifications in beta-catenin localization, nor the expression of beta-catenin transcriptional target genes, were observed in Apc(Min/+) mammary tissues; however, tissues from lactating Apc(Min/+) mice had a significantly altered epithelial architecture, including disrupted localization of junctional proteins and polarization. Consistent with these findings, APC knockdown in non-transformed mouse mammary epithelial cells in vitro resulted in altered monolayer formation and proliferation without changes in beta-catenin-mediated transcription. These results suggest that APC expression is tightly regulated during mammary gland development and is required for normal mammary homeostasis and tumor suppression primarily through maintaining epithelial integrity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenomatous Polyposis Coli Protein / genetics
  • Adenomatous Polyposis Coli Protein / metabolism*
  • Animals
  • Apoptosis / physiology
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Cell Proliferation
  • Epithelial Cells* / cytology
  • Epithelial Cells* / metabolism
  • Epithelium / anatomy & histology
  • Epithelium / metabolism
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation*
  • Gene Knockdown Techniques
  • Humans
  • Male
  • Mammary Glands, Animal* / anatomy & histology
  • Mammary Glands, Animal* / growth & development
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Microarray Analysis
  • Phenotype
  • Precancerous Conditions / metabolism
  • Precancerous Conditions / pathology
  • Pregnancy
  • beta Catenin / genetics
  • beta Catenin / metabolism

Substances

  • Adenomatous Polyposis Coli Protein
  • beta Catenin