Abstract A32: In vivo imaging of ERK activity of mouse breast cancer cells reveals heterogeneity in response to anti-cancer drugs and tumor forming capacity

The Ras-Raf-MEK-ERK pathway is critical for normal physiological development and for carcinogenesis. However, the activity of this signaling cascade has never been examined in living cancer tissues due to technical difficulty. We have recently developed transgenic mice expressing a Förster resonance energy transfer (FRET) biosensor for ERK, which allows us to monitor cellular ERK activity in living tissues under two-photon (2P) microscopes. To study the role of ERK in mammary tumors, we crossed MMTV-Neu mice with the mice expressing the ERK FRET biosensor and observed in vivo under 2P. In the primary mammary tumors, the ERK activity exhibited significant divergence among the tumor cells. Such heterogeneity was significantly diminished in the secondary tumor cells. A MEK inhibitor PD0325901 and an EGFR/HER2 inhibitor Lapatinib suppressed ERK in both the primary mammary tumor cells and the secondary mammary tumor cells. Interestingly, we found that a small number of cells with low ERK activity in primary tumors that did not respond to Lapatinib. We sorted cells depending on ERK activity and obtained ERKlow and ERKhigh population.The ERKlow population exhibited higher tumorsphere formation in nonadherent culture condition and tumor formation in syngeneic mice. Notably, the tumors developed from ERKlow cells exhibited heterogeneous ERK activity similar to primary tumors. Taken together, our results suggest that the heterogeneous ERK activity might be related to cancer stem cell in tumors. Citation Format: Yuka Kumagai, Michiyuki Matsuda. In vivo imaging of ERK activity of mouse breast cancer cells reveals heterogeneity in response to anti-cancer drugs and tumor forming capacity. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr A32.