Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 108, Issue 33, Pages 13653-13658Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1103360108
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Funding
- National Natural Science Foundation of China [30872172, 30771844]
- program for Changjiang Scholars and Innovative Research Team in University in China [IRT1076]
- National Key Scientific and Technological Project [2011ZX09307-001-04]
- Tianjin Science and Technology Committee Foundation [08ZCGHZ02000, 08JCZDJC23600, 09ZCZDSF04800, 09ZCZDSF04700]
- Major State Basic Research Development Program of China [2009CB918903]
- National Institutes of Health through M. D. Anderson Cancer Center [CA016672]
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We have evaluated and provided evidence that the ryanodine receptor 3 gene (RYR3), which encodes a large protein that forms a calcium channel, is important for the growth, morphology, and migration of breast cancer cells. A putative binding site for microRNA-367 (miR-367) exists in the 3'UTR of RYR3, and a genetic variant, rs1044129 A. G, is present in this binding region. We confirmed that miR-367 regulates the expression of a reporter gene driven by the RYR3 3'UTR and that the regulation was affected by the RYR3 genotype. A thermodynamic model based on base pairing and the secondary structure of the RYR3 mRNA and miR-367 miRNA showed that miR-367 had a higher binding affinity for the A genotype than for the G genotype. The rs1044129 SNP was genotyped in 1,532 breast cancer cases and 1,600 healthy Chinese women. The results showed that compared with the AA genotype, G was a risk genotype for breast cancer development and was also associated with breast cancer calcification and poor survival. Thus, rs1044129 is a unique SNP that resides in a miRNA-gene regulatory loop that affects breast cancer risk, calcification, and survival.
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