The nuclear receptor coactivator amplified in breast cancer-1 is required for Neu (ErbB2/HER2) activation, signaling, and mammary tumorigenesis in mice

Cancer Res. 2008 May 15;68(10):3697-706. doi: 10.1158/0008-5472.CAN-07-6702.


Overexpression of the oncogene amplified in breast cancer 1 (AIB1)/steroid receptor coactivator-3 (SRC-3) induces mammary tumorigenesis in mice. In breast cancer, high levels of AIB1/SRC-3 and the growth factor receptor HER2/neu predict resistance to endocrine therapy and poor outcome. However, a mechanistic relationship between AIB1/SRC-3 and HER2/neu in the development of breast cancer has not been shown. Here, we show that deletion of one allele of SRC-3 significantly delays Neu-induced mammary tumor development in mice. Homozygous deletion of SRC-3 in mice completely prevents Neu-induced tumor formation. By ages 3 to 4 months, Neu/SRC-3(+/-) mice exhibit a noticeable reduction in lateral side-bud formation, accompanied by reduced cellular levels of phosphorylated Neu compared with Neu/SRC-3(wt) mice. In Neu-induced tumors, high levels of SRC-3, phosphorylated Neu, cyclin D1, cyclin E, and proliferating cell nuclear antigen expression are observed, accompanied by activation of the AKT and c-Jun NH(2) kinase (JNK) signaling pathways. In comparison, phosphorylated Neu, cyclin D1, and cyclin E are significantly decreased in Neu/SRC-3(+/-) tumors, proliferation is reduced, and AKT and JNK activation is barely detectable. Our data indicate that AIB1/SRC-3 is required for HER2/neu oncogenic activity and for the phosphorylation and activation of the HER2/neu receptor. We predict that reducing AIB1/SRC-3 levels or activity in the mammary epithelium could potentiate therapies aimed at inhibiting HER2/neu signaling in breast cancer.

Publication types

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

MeSH terms

  • Alleles
  • Animals
  • Cell Proliferation
  • Epithelium / metabolism
  • Gene Deletion
  • Histone Acetyltransferases / genetics*
  • Histone Acetyltransferases / metabolism
  • Histone Acetyltransferases / physiology*
  • MAP Kinase Kinase 4 / metabolism
  • Mammary Neoplasms, Animal / genetics*
  • Mammary Neoplasms, Animal / metabolism*
  • Mice
  • Mice, Transgenic
  • Models, Biological
  • Nuclear Receptor Coactivator 3
  • Phosphorylation
  • Receptor, ErbB-2 / metabolism*
  • Signal Transduction
  • Trans-Activators / genetics*
  • Trans-Activators / metabolism
  • Trans-Activators / physiology*


  • Trans-Activators
  • Histone Acetyltransferases
  • Ncoa3 protein, mouse
  • Nuclear Receptor Coactivator 3
  • Receptor, ErbB-2
  • MAP Kinase Kinase 4