Low expression of cytosolic NOTCH1 predicts poor prognosis of breast cancer patients

Yi-Ling Chen; Kuo-Ting Lee; Chih-Yang Wang; Che-Hung Shen; Sheau-Chiann Chen; Wei-Pang Chung; Ya-Ting Hsu; Yao-Lung Kuo; Pai-Sheng Chen; Chun Hei Antonio Cheung; Chih-Peng Chang; Meng-Ru Shen; Hui-Ping Hsu

Low expression of cytosolic NOTCH1 predicts poor prognosis of breast cancer patients

Am J Cancer Res. 2022 May 15;12(5):2084-2101. eCollection 2022.

Authors

Yi-Ling Chen¹, Kuo-Ting Lee², Chih-Yang Wang^{3

4}, Che-Hung Shen⁵, Sheau-Chiann Chen⁶, Wei-Pang Chung^{7

8

9}, Ya-Ting Hsu¹⁰, Yao-Lung Kuo², Pai-Sheng Chen^{4

11}, Chun Hei Antonio Cheung^{4

12}, Chih-Peng Chang^{4

13}, Meng-Ru Shen^{12

14}, Hui-Ping Hsu^{2

6}

Affiliations

¹ Department of Health and Nutrition, Chia Nan University of Pharmacy and Science Tainan 71710, Taiwan.
² Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University Tainan 70403, Taiwan.
³ Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University Tainan 70101, Taiwan.
⁴ Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University Tainan 70101, Taiwan.
⁵ National Institute of Cancer Research, National Health Research Institute Tainan 70456, Taiwan.
⁶ Department of Biostatistics, Vanderbilt University Medical Center Nashville, Tennessee 37232, United States.
⁷ Institute of Clinical Medicine, College of Medicine, National Cheng Kung University Tainan 70101, Taiwan.
⁸ Department of Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University Tainan 70403, Taiwan.
⁹ Center of Applied Nanomedicine, National Cheng Kung University Tainan, Taiwan.
¹⁰ Division of Hematology, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University Tainan 70403, Taiwan.
¹¹ Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University Tainan 70101, Taiwan.
¹² Department of Pharmacology, College of Medicine, National Cheng Kung University Tainan 70101, Taiwan.
¹³ Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University Tainan 70101, Taiwan.
¹⁴ Department of Obstetrics and Gynecology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University Tainan 70403, Taiwan.

PMID: 35693094
PMCID: PMC9185622

Abstract

The incidence of breast cancer is increasing, and is one of the leading causes of cancer death worldwide. Dysregulation of NOTCH1 signaling is reported in breast cancer. In present study, bioinformatics was utilized to study the expression of NOTCH1 gene in breast cancer from public databases, including the Kaplan-Meier Plotter, PrognoScan, Human Protein Atlas, and cBioPortal. The relationship between NOTCH1 mRNA expression and survival of patients was inconsistent in public databases. In addition, we performed immunohistochemistry (IHC) staining of 135 specimens from our hospital. Lower cytoplasmic staining of NOTCH1 protein was correlated with cancer recurrence, bone metastasis, and a worse disease-free survival of patients, especially those with estrogen receptor-positive and human epidermal growth factor receptor 2-positive (HER2⁺) cancers. In TCGA breast cancer dataset, lower expression of NOTCH1 in breast cancer specimens was correlated with higher level of CCND1 (protein: cyclin D1). Decreased expression of NOTCH1 was correlated with lower level of CCNA1 (protein: cyclin A1), CCND2 (protein: cyclin D2), CCNE1 (protein: cyclin E1), CDK6 (protein: CDK6), and CDKN2C (protein: p18). In conclusion, NOTCH1 mRNA expression is not consistently correlated with clinical outcomes of breast cancer patients. Low cytoplasmic expression of NOTCH1 in IHC study is correlated with poor prognosis of breast cancer patients. Cytoplasmic localization of NOTCH1 protein failed to initial oncogenic signaling in present study. Expression of NOTCH1 mRNA was discordant with cell cycle-related genes. Regulation of NOTCH1 in breast cancer involves gene expression, protein localization and downstream signaling.

Keywords: Breast cancer; NOTCH1; bioinformatics; cell cycle; protein localization; recurrence-free survival.