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

Wei-Hwa Lee, Li-Ching Chen, Chia-Jung Lee, Chi-Cheng Huang, Yuan-Soon Ho, Po-Sheng Yang, Chi-Tang Ho, Hang-Lung Chang, I-Hsuan Lin, Hui-Wen Chang, Yun-Ru Liu, Chih-Hsiung Wu, Shih-Hsin Tu

Research output: Contribution to journalArticlepeer-review

8 Citations (Scopus)

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 × 10 3/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.

Original languageEnglish
Pages (from-to)615-630
Number of pages16
JournalInternational Journal of Cancer
Volume144
Issue number3
DOIs
Publication statusPublished - Feb 1 2019

Keywords

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

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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