Use of MMTV-Neu/P53 KO Transgenic Mice To Screen for Potential Chemopreventive Agents.

Abstract

Abstract The MMTV-Neu transgenic model of mammary cancer was developed almost 20 years ago in which the 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 administered to virgin female MMTV-Neu/P53 KO mice beginning when they were 60 days of age. Initiation of treatment with the agents was later than that typically employed by other investigators (e.g., 35 days of age). Mice were monitored until 360 days of age. In agreement with Brown and colleagues (e.g., Cancer Research 62, 6376-6380, 2002), it was found that 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. We also observed that a wide variety of agents were ineffective; including Atorvastatin, rosiglitazone (a PPAR gamma agonist), SAHA (an HDAC inhibitor), 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. As previously shown by our lab in an ER+ rat model of mammary cancer, effective agents (e.g., Iressa 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 predict 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. Thus, this model is useful in identifying agents that will prevent the development of human breast cancers that over-express Neu. This is important since Neu over-expressing ER- cancers have a relatively poor prognosis, and Neu over-expressing ER+ tumors are relatively unresponsive to standard hormonal therapies (e.g., tamoxifen and aromatase inhibitors). Supported by NCI contract HHSN261200433001C. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1042.