Abstract B49: Use of MMTV-Neu/P53 KO transgenic mice to screen for potential chemopreventive agents

Abstract

The MMTV-Neu transgenic model of mammary cancer was developed almost 20 years ago in which mice develop Neu over-expressing ER^- mammary cancers. Since human ER^- Neu over-expressing mammary cancers often also have mutations in P53, a heterozygous KO of P53 was incorporated into the model. We used this model to examine a wide variety of potential chemopreventive agents. The agents were routinely administered to virgin female MMTV-Neu/P53 KO mice beginning when they were 60 days of age. Initiation at this time is somewhat later than is often employed in other laboratories (i.e., agents are typically started when mice are roughly 5-6 weeks of age). Mice were routinely monitored until 360 days of age. In agreement with Brown and colleagues (e.g., Cancer Res. 62: 6376-6380, 2002), it was found both RXR agonists (Targretin, UAB-30) and EGFR 1 and/or 2 inhibitors (Tarceva, Lapatinib) were highly effective in preventing the development of these cancers. More surprisingly, tamoxifen which is ineffective as a therapeutic agent against ER^- breast cancer in women was effective in this model. It was also observed that a wide variety of agents were ineffective; including Atorvastatin, rosiglitazone (a PPAR gamma agonist), SAHA (an HDAC inhibitor), metformin, and a soy isoflavones mixture. In separate studies, mice bearing small palpable mammary tumors were treated for five days with these various agents, and examined for alterations in potential biomarkers; including proliferation. Effective agents (e.g., Iressa, Tarceva, and Targretin) strongly inhibited cancer cell proliferation, whereas ineffective agents failed to significantly inhibit proliferation. Thus, such a short-term assay might be employed to determine potential chemopreventive compounds. Short-term treatment with the EGFR inhibitors also decreased levels of expression of phosphorylated EGFR and downstream proteins; e.g., AKT/ERK. Supported by NCI contract number HHSN26120043301C.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):B49.