Heterogeneity in ERK activity as visualized by in vivo FRET imaging of mammary tumor cells developed in MMTV-Neu mice

• Published in: Oncogene Vol. 34; no. 8; pp. 1051 - 1057
• Main Authors: Kumagai, Y, Naoki, H, Nakasyo, E, Kamioka, Y, Kiyokawa, E, Matsuda, M
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 19.02.2015; Nature Publishing Group
• Subjects: 631/1647/527/2047; 631/67/1347; 631/67/71; 631/80/86; Animals; Antineoplastic Agents - pharmacokinetics; Apoptosis; Benzamides - pharmacokinetics; Biosensors; Breast cancer; Cancer; Care and treatment; Cell Biology; Cell self-renewal; Cellular biology; Computer Systems; Diagnosis; Diphenylamine - analogs & derivatives; Diphenylamine - pharmacokinetics; Epidermal growth factor; Extracellular signal-regulated kinase; Extracellular Signal-Regulated MAP Kinases - antagonists & inhibitors; Extracellular Signal-Regulated MAP Kinases - metabolism; Female; Fluorescence Resonance Energy Transfer; Genes, erbB-2; Genetic aspects; Human Genetics; Internal Medicine; Mammary gland; Mammary Neoplasms, Experimental - genetics; Mammary Neoplasms, Experimental - metabolism; Mammary Neoplasms, Experimental - pathology; Mammary Tumor Virus, Mouse - genetics; Medicine; Medicine & Public Health; Metabolic pathways; Mice; Mice, Transgenic; Molecular Imaging - methods; Neoplasm Metastasis; Oncology; Physiological aspects; Protein Kinase Inhibitors - pharmacokinetics; Raf protein; Risk factors; short-communication; Stem cell transplantation; Stem cells; Studies; Transgenic animals; Transgenic mice; Tumor cells; Tumors; Japan
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2014.28

Human epidermal growth factor receptor2/Neu, which is overexpressed in about 30% of human breast cancers, transduces growth signals in large part via the Ras–Raf–MEK–ERK pathway. Nevertheless, it is a matter of controversy whether high ERK activity in breast cancer tissues correlates with better or worse prognosis, leaving the role of ERK activity in the progression of breast cancers unresolved. To address this issue, we live-imaged ERK activity in mammary tumors developed in mouse mammary tumor virus-Neu transgenic mice, which had been crossed with transgenic mice expressing a Förster resonance energy transfer biosensor for ERK. Observation of the tumor by two-photon microscopy revealed significant heterogeneity in ERK activity among the mammary tumor cells. The level of ERK activity in each cell was stable up to several hours, implying a robust mechanism that maintained the ERK activity within a limited range. By sorting the mammary tumor cells on the basis of their ERK activity, we found that ERK high cells less efficiently generated tumorspheres in vitro and tumors in vivo than did ERK low cells. In agreement with this finding, the expressions of the cancer stem cell markers CD49f, CD24 and CD61 were decreased in ERK high cells. These observations suggest that high ERK activity may suppress the self-renewal of mammary cancer stem cells.