Dissecting genetic requirements of human breast tumorigenesis in a tissue transgenic model of human breast cancer in mice

Proc Natl Acad Sci U S A. 2009 Apr 28;106(17):7022-7. doi: 10.1073/pnas.0811785106. Epub 2009 Apr 15.


Breast cancer development is a complex pathobiological process involving sequential genetic alterations in normal epithelial cells that results in uncontrolled growth in a permissive microenvironment. Accordingly, physiologically relevant models of human breast cancer that recapitulate these events are needed to study cancer biology and evaluate therapeutic agents. Here, we report the generation and utilization of the human breast cancer in mouse (HIM) model, which is composed of genetically engineered primary human breast epithelial organoids and activated human breast stromal cells. By using this approach, we have defined key genetic events required to drive the development of human preneoplastic lesions as well as invasive adenocarcinomas that are histologically similar to those in patients. Tumor development in the HIM model proceeds through defined histological stages of hyperplasia, DCIS to invasive carcinoma. Moreover, HIM tumors display characteristic responses to targeted therapies, such as HER2 inhibitors, further validating the utility of these models in preclinical compound testing. The HIM model is an experimentally tractable human in vivo system that holds great potential for advancing our basic understanding of cancer biology and for the discovery and testing of targeted therapies.

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology*
  • Cell Transformation, Neoplastic / genetics*
  • Cell Transformation, Neoplastic / metabolism
  • Cell Transformation, Neoplastic / pathology*
  • Cyclin D1 / metabolism
  • Disease Models, Animal
  • Disease Progression
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Mice
  • Neoplasm Invasiveness
  • Phosphatidylinositol 3-Kinases / metabolism
  • RNA Interference
  • Receptor, ErbB-2 / antagonists & inhibitors
  • Receptor, ErbB-2 / genetics
  • Receptor, ErbB-2 / metabolism
  • Simian virus 40 / genetics
  • Simian virus 40 / metabolism
  • Telomerase / metabolism
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism
  • Xenograft Model Antitumor Assays
  • ras Proteins / genetics
  • ras Proteins / metabolism


  • Tumor Suppressor Protein p53
  • Cyclin D1
  • Phosphatidylinositol 3-Kinases
  • Receptor, ErbB-2
  • Telomerase
  • ras Proteins