Abstract 3048: High frequencies of centrosome amplification in MMTV-Her2/Neu pre-malignant mammary lesions and in Her2+ breast cancer cells suggest that centrosome amplification is involved in Her2-dependent breast cancer biogenesis

Abstract

Abstract Centrosome amplification (CA) is a major force in cancer initiation and progression, as it generates aneuploidy and chromosome instability. Observations in breast tumors show that adenocarcinomas have a higher frequency of centrosome defects when compared to normal breast tissue. Similar phenotypes are also found in pre-malignant lesions and in pre-invasive in situ ductal carcinoma, suggesting that these aberrations occur early in breast carcinogenesis. Identification of the pathways and regulatory molecules involved in the generation of CA is essential to understanding the role of CA in breast tumorigenesis. Our published results showed that CA is specific to the Her2 effector Ras at mammary pre-malignancy and in tumorigenesis. Due to the strong association between Her2 over-expression and CA in human breast cancers, our goal is to identify cell and centrosome cycle regulators that are de-regulated by aberrant Her2 signaling in human and mouse mammary epithelial cells. Our results show breast cancer cells over-expressing Her2 and pre-malignant mouse mammary hyperplasias expressing Her2/Neu harbor CA. In Her2+ cells that display a plethora of genetic alterations, this process is dependent on Her2, as revealed by shRNA and shRNA downregulation of Her2. Human breast cancer cells expressing Her2 show up-regulation of cyclin D1 and other important centrosome regulatory molecules. In fact, abrogation of Cdk4 or Cdk6, catalytic partners of cyclin D1 reduced the frequencies of CA in Her2+ cells. In contrast, downregulation of Cdk2 did not affect CA. We want to elucidate the mechanism responsible for CA in Her2+ breast cancers. Cells overexpressing Her2 also display increased frequencies of binucleation, suggesting a defect in cytokinesis. We propose that in Her2+ cells, Cdk4 signals CA through either by hyperphosphorylation of NPM at Thr199, a site that negatively regulates centrosome duplication, and/or through the Rb/E2F pathway. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3048. doi:1538-7445.AM2012-3048