FE65 in breast cancer and its clinicopathological significance

Junyao Xu; Erina Iwabuchi; Yasuhiro Miki; Ayako Kanai; Takanori Ishida; Hironobu Sasano

doi:10.1007/s12282-021-01291-4

FE65 in breast cancer and its clinicopathological significance

Breast Cancer. 2022 Jan;29(1):144-155. doi: 10.1007/s12282-021-01291-4. Epub 2021 Sep 8.

Authors

Junyao Xu¹, Erina Iwabuchi¹, Yasuhiro Miki^{1

2}, Ayako Kanai^{1

3}, Takanori Ishida³, Hironobu Sasano⁴

Affiliations

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.

PMID: 34498219
DOI: 10.1007/s12282-021-01291-4

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.

Keywords: APP; Breast cancer; ER α; FE65; p-APP.

MeSH terms

Adult
Aged
Aged, 80 and over
Amyloid beta-Protein Precursor / metabolism
Breast Neoplasms / metabolism*
Breast Neoplasms / mortality
Breast Neoplasms / pathology
Cell Line, Tumor
Cell Movement
Cell Proliferation
Disease-Free Survival
Estrogen Receptor alpha / metabolism
Female
Humans
Lymphatic Metastasis
Middle Aged
Nerve Tissue Proteins / metabolism*
Nuclear Proteins / metabolism*

Substances

APBB1 protein, human
Amyloid beta-Protein Precursor
Estrogen Receptor alpha
Nerve Tissue Proteins
Nuclear Proteins