Junyao Xu1, Erina Iwabuchi1, Yasuhiro Miki1,2, Ayako Kanai1,3, Takanori Ishida3, Hironobu Sasano4. 1. Department of Pathology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, 980- 8575, Japan. 2. Department of Disaster Obstetrics and Gynecology, International Research Institute of Disaster Science (IRIDes), Tohoku University, Sendai, Japan. 3. Department of Breast and Endocrine Surgical Oncology, Tohoku University Graduate School of Medicine, Sendai, Japan. 4. Department of Pathology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, 980- 8575, Japan. hsasano@patholo2.med.tohoku.ac.jp.
Abstract
BACKGROUND: Transcription coregulator adapter protein FE65 is well known to play pivotal roles in pathogenesis of Alzheimer's disease by regulating amyloid precursor protein (APP) expression and processing. APP was recently reported to be also involved in development of human malignancies. Therefore, in this study, we studied FE65 status in different subtypes of human breast cancer and correlated the results with cell proliferation and migration of carcinoma cells and clinicopathological features of breast cancer patients to explore its biological and clinical significance in breast cancer. METHODS: We first immunolocalized FE65 and APP in 138 breast cancer patients and correlated the results with their tumor grade. Then, we did further exploration by proximity ligation assay, WST-8, and wound-healing assay. RESULTS: FE65 immunoreactivity in carcinoma cells was significantly associated with lymph-node metastasis, ERα, and high pathological N factor. APP immunoreactivity was significantly positively correlated with high pathological N factor. FE65, APP, and p-APP were all significantly correlated with shorter disease-free survival of breast cancer patients. In addition, the status of FE65 was significantly associated with overall survival. Results of in vitro analysis revealed that FE65 promoted the migration and proliferation of T-47D and ZR-75-1 breast carcinoma cells. In situ proximity ligation assay revealed that FE65 could bind to APP in the cytoplasm. FE65 was also associated with APP and ERα in carcinoma cells, suggesting their cooperativity in promoting carcinoma cell proliferation and migration. APP was also significantly associated with adverse clinical outcome of the patients. CONCLUSIONS: This is the first study to explore the clinical significance of FE65 in human breast cancer. The significant positive correlation of FE65 with poor clinical outcome, direct binding to APP, and promotion of carcinoma cell proliferation and migration indicated that FE65-APP pathway could serve as the potential candidate of therapeutic intervention in breast cancer patients.
BACKGROUND: Transcription coregulator adapter protein FE65 is well known to play pivotal roles in pathogenesis of Alzheimer's disease by regulating amyloid precursor protein (APP) expression and processing. APP was recently reported to be also involved in development of human malignancies. Therefore, in this study, we studied FE65 status in different subtypes of human breast cancer and correlated the results with cell proliferation and migration of carcinoma cells and clinicopathological features of breast cancer patients to explore its biological and clinical significance in breast cancer. METHODS: We first immunolocalized FE65 and APP in 138 breast cancer patients and correlated the results with their tumor grade. Then, we did further exploration by proximity ligation assay, WST-8, and wound-healing assay. RESULTS: FE65 immunoreactivity in carcinoma cells was significantly associated with lymph-node metastasis, ERα, and high pathological N factor. APP immunoreactivity was significantly positively correlated with high pathological N factor. FE65, APP, and p-APP were all significantly correlated with shorter disease-free survival of breast cancer patients. In addition, the status of FE65 was significantly associated with overall survival. Results of in vitro analysis revealed that FE65 promoted the migration and proliferation of T-47D and ZR-75-1 breast carcinoma cells. In situ proximity ligation assay revealed that FE65 could bind to APP in the cytoplasm. FE65 was also associated with APP and ERα in carcinoma cells, suggesting their cooperativity in promoting carcinoma cell proliferation and migration. APP was also significantly associated with adverse clinical outcome of the patients. CONCLUSIONS: This is the first study to explore the clinical significance of FE65 in human breast cancer. The significant positive correlation of FE65 with poor clinical outcome, direct binding to APP, and promotion of carcinoma cell proliferation and migration indicated that FE65-APP pathway could serve as the potential candidate of therapeutic intervention in breast cancer patients.
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