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Int J Cancer. 2019 Feb 1;144(3):615-630. doi: 10.1002/ijc.31788. Epub 2018 Nov 21.

DNA primase polypeptide 1 (PRIM1) involves in estrogen-induced breast cancer formation through activation of the G2/M cell cycle checkpoint.

Lee WH1,2, Chen LC3,4,5, Lee CJ6, Huang CC7,8,9, Ho YS5,6,10,11, Yang PS12,13, Ho CT14, Chang HL15, Lin IH5, Chang HW10, Liu YR5,16, Wu CH7,15, Tu SH3,4,7.

Author information

1
Department of Pathology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
2
Department of Pathology, Taipei Medical University-Shuang Ho Hospital, New Taipei City, Taiwan.
3
Breast Medical Center, Taipei Medical University Hospital, Taipei, Taiwan.
4
Taipei Cancer Center, Taipei Medical University, Taipei, Taiwan.
5
TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan.
6
Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.
7
Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
8
School of Medicine, College of Medicine, Fu-Jen Catholic University, New Taipei City, Taiwan.
9
Department of Surgery, Fu-Jen Catholic University Hospital, New Taipei City, Taiwan.
10
Department of Laboratory Medicine, Taipei Medical University Hospital, Taipei, Taiwan.
11
School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
12
Department of Surgery, Mackay Memorial Hospital, Taipei, Taiwan.
13
Department of Medicine, Mackay Medical College, New Taipei City, Taiwan.
14
Department of Food Science, Rutgers University, New Brunswick, NJ, USA.
15
Department of General Surgery, En Chu Kong Hospital, New Taipei City, Taiwan.
16
Joint Biobank, Office of Human Research, Taipei Medical University, Taipei, Taiwan.

Abstract

The DNA primase polypeptide 1 (PRIM1) is responsible for synthesizing small RNA primers for Okazaki fragments generated during discontinuous DNA replication. PRIM1 mRNA expression levels in breast tumor samples were detected by real-time PCR analysis. Xenografted tumor model was established to study the carcinogenic role of PRIM1 and its potential therapeutic applications. The average PRIM1 mRNA (copy number × 103 /μg) expression was 4.7-fold higher in tumors than in normal tissue (*p = 0.005, n = 254). PRIM1 was detected preferentially at a higher level (>40-fold) in poorly differentiated tumor tissues (n = 46) compared with more highly differentiated tumors tissues (n = 10) (*p = 0.005). Poor overall survival rate was correlated to the estrogen receptor positive (ER+, n = 20) patients with higher PRIM1 expression when compare to the ER- (n = 10) patients (Chi Square test, p = 0.03). Stable expression of PRIM1-siRNA in the ER+ BT-474 cells-xenograft tumors significantly reduced tumor volume in SCID mice (*p = 0.005). The anti-tumoral effects of inotilone isolated from Phellinus linteus was tested and had significant effects on the inhibition of PRIM1 protein expression in ER+ breast cancer cells. In vivo study was performed by administering inotilone (10 mg/kg, twice a week for 6 weeks), which resulted in significantly reduced BT-474-xenografted tumor growth volume compared with control (n =5 per group, *p < 0.05). This study provides evidences for the prognostic effects of PRIM1 with poor overall survival rate in the ER+ patients and will be valuable to test for therapeutic purpose.

KEYWORDS:

DNA primase polypeptide 1; breast cancer; cancer prevention; inotilone

PMID:
30097999
DOI:
10.1002/ijc.31788
[Indexed for MEDLINE]
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