Herceptin-sensitivity of HER2-transgenic mouse mammary tumors

The long-term goal of our work is to better understand the mechanisms of Herceptin action and resistance. Toward that end, we have produced transgenic mice that express HER2 under the control of the mouse mammary tumor virus (MMTV) promoter. Transgenic mouse models offer the advantage of having immune system components that may be important in the action of antibodies but are lacking in immunodeficient hosts. ErbB2 transgenic mice have been produced by Muller and colleagues using the rat homolog neu, which does not bind Herceptin. Therefore, we made mice using the human version, HER2. These mice express HER2 in the mammary gland at very high levels and develop HER2-positive mammary tumors within 6–8 months. Several tumors have been propagated as allografts in wild-type mice by implanting a small piece of tumor into the mammary fat pad. Cohorts of mice bearing the same tumor line were then treated with 4D5, the murine version of Herceptin, or vehicle. Using this approach, we found that several tumor lines are completely Herceptin resistant, others are growth inhibited, and one regresses completely. As observed previously in tumors from neu transgenic mice, all of our HER2 tumors contain small deletions in the juxtamembrane region of the HER2 transcript. Within a tumor line, each mutation is unique and remains stable on continued passage. It is unclear, however, whether such mutations are responsible for determining Herceptin sensitivity. Gene expression profiling between the highly sensitive tumor line (F2-1282) and a Herceptin-resistant line (Fo5) revealed a large number of differences that could contribute to resistance. Gene expression profiling is also being used to identify changes that take place in F2-1282, the Herceptin-sensitive tumor, when it is exposed to Herceptin/4D5. In summary, like individual breast cancer patients, tumors from MMTV-HER2 mice display the entire spectrum of responsiveness to Herceptin/4D5, from resistant to complete regression, and therefore may help provide insights into cofactors that are important for Herceptin activity.