Journal
INTERNATIONAL JOURNAL OF CANCER
Volume 144, Issue 3, Pages 615-630Publisher
WILEY
DOI: 10.1002/ijc.31788
Keywords
breast cancer; DNA primase polypeptide 1; inotilone; cancer prevention
Categories
Funding
- Health and Welfare surcharge of tobacco products grant [MOHW107-TDU-B-212-11401]
- Ministry of Science and Technology, R.O.C. [MOST 106-2320-B-038-061-MY3, MOST105-2320-B-038-053-MY3, MOST106-2314-B-038-053-MY3, MOST106-2320-B-038-046]
- Taipei Medical University Shuang Ho Hospital [105TMU-SHH-08]
- TMU Research Center of Cancer Translational Medicine from The Featured Areas Research Center Program by the Ministry of Education (MOE)
- Taipei Medical University-Shuang Ho Hospital [105TMU-SHH-08]
- Ministry of Science and Technology [MOST105-2320-B-038-053-MY3, MOST106-2314-B-038-053-MY3, MOST106-2320-B-038-046, MOST104-2314-B-038-059-MY3, MOST106-2320-B-038-061-MY3]
- Health and Welfare Surcharge of Tobacco Products [MOHW107-TDU-B-212-114014]
- Ministry of Education (MOE)
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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 x 10(3)/mu g) 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.
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