Oncogenic and tumor-suppressive mouse models for breast cancer engaging HER2/neu

Abstract

The human c-ErbB2 (HER2) gene is amplified in ~20 % of human breast cancers (BCs), but the protein is overexpressed in ~30% of the cases indicating that multiple different mechanisms contribute to HER2 overexpression in tumors. It has long been used as a molecular marker of BC for sub-categorization for the prediction of prognosis, and determination of therapeutic strategies. In comparison to ER(+) BCs, HER2(+) BCs are more invasive, but the patients respond to monoclonal antibody therapy with trastuzumab or tyrosine kinase inhibitors at least at early stages. To understand the pathophysiology of HER2-driven carcinogenesis and test HER2-targeting therapeutic agents in vivo, numerous mouse models have been created that faithfully reproduce HER2(+) BCs in mice. They include MMTV-neu (active mutant or wild type, rat neu or HER2) models, neu promoter-driven neuNT-transgenic mice, neuNT-knock-in mice at the neu locus, and doxycycline-inducible neuNT-transgenic models. HER2/neu activates the Phosphatidylinositol-3 kinase-AKT-NF-κB pathway to stimulate the mitogenic cyclin D1/Cdk4-Rb-E2F pathway. Of note, overexpression of HER2 also stimulates the cell autonomous Dmp1-Arf-p53 tumor suppressor pathway to quench oncogenic signals to prevent the emergence of cancer cells. Hence tumor development by MMTV-neu mice was dramatically accelerated in mice that lack Dmp1, Arf or p53 with invasion and metastasis. Expressions of neuNT under the endogenous promoter underwent gene amplification, closely recapitulating human HER2(+) BCs. MMTV-HER2 models have been shown to be useful to test humanized monoclonal antibodies to HER2. These mouse models will be useful for the screening of novel therapeutic agents against BCs with HER2 overexpression.

Aberrant expression of ETS1 and ETS2 proteins in cancer

“…Many of the transcription factors that bind to mtp53 have also been shown to interact with wild type p53 (WTp53) (E2F1:DP [104], NF-Y, vitamin D3-responsive element [VDR], and SP1). Early studies showed that mtp53 regulates gene expression via recruitment of transcription factors on the MDR1 promoter (165, 166).…”

Novel treatment strategies for patients with HER2‑positive breast cancer who do not benefit from current targeted therapy drugs (Review)

“…The phosphatidylinositol 3-kinase (PI3K) pathway and the Ras/Raf mitogen-activated protein kinase (MAPK) pathway are the most fully investigated of these pathways, both of which may contribute to the acquired resistance against targeted therapy drugs (8-10). Related research has identified that inhibition of the PI3K-Akt pathway with PI3K inhibitors is effective to reverse tumor growth (11)(12)(13). When the HER2 proto-oncogene undergoes mutation and conversions into the HER2 oncogene (14), HER2 receptor protein is highly expressed at the cell membrane, and multiple downstream signaling pathways are excessively activated, resulting in uncontrollable cell growth, repeated division of cells, and altered adhesion properties (7,14,15).…”

Stabilization of the p53-DNA Complex by the Nuclear Protein Dmp1α

“…Mitogenic signals from oncogenic Ras (39) and HER2/neu (19, 40) have been shown to activate the Dmp1 promoter (39, 41) while physiological mitogens as well as genotoxic stimuli mediated by NF-κB cause repression (42). It has been theorized that the Dmp1 protein acts as a tumor suppressor by directly transactivating the Arf promoter, thereby inducing Arf-, p53-dependent cell cycle arrest (20, 33, 34, 43).…”