Abstract #3045

HER2 (ErbB2/Neu in rodents) is overexpressed in a number of breast cancers and it activates several intracellular signaling pathways by recruiting adaptor proteins. Among them, Shc or Gab2 signaling mediates ErbB2/Neu-induced mammary tumor progression. HER2 activates the transcription factors STAT5A/B but their contribution to the etiology of breast cancer remains to be elucidated. STAT5 mediates signals from a wide variety of cytokine receptors, including the EGFR and ErbB4. Further, constitutive activation of STAT5 has been observed in human breast cancer, leukemia and many solid tumors. To address whether STAT5 mediates HER2/ErbB2/Neu-induced breast cancer progression, both Stat5 genes were deleted specifically in ErbB2/Neu oncogene (known as HER2 in human)-expressing mammary epithelial cells in mice. Briefly, transgenic mice carrying floxed Stat5 alleles (Stat5fl/fl mice) were mated with transgenic MMTV/NIC mice expressing both activated Neu/ErbB2 and Cre recombinase from the same bicistronic transcript due to the presence of an internal ribosome entry site (IRES) between the two cDNA sequences (NIC) under the control of mouse mammary tumor virus (MMTV) long terminal repeat. Whole mount staining of mammary tissue of MMTV/NIC mice demonstrated that mammary glands of control virgin NIC mice (MMTV/NIC;Stat5+/+) exhibited hyperplastic lesions at 5 months of age, while no lesions were detected in NIC mice that lacked STAT5 (MMTV/NIC;Stat5fl/fl). Histological analysis revealed the absence of hyperplastic or neoplastic lesions in MMTV/NIC;Stat5fl/fl mammary glands. These results indicate that inactivation of Stat5 results in the absence of hyperplasias in spite of overexpression of ErbB2/Neu in mammary epithelium and suggest that activation of STAT5 contributes to the development of HER2-induced breast cancer.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3045.

Thirty-first San Antonio Breast Cancer Symposium Dec 10-14, 2008; San Antonio, TX