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Genetic variation in the chromosome 17q23 amplicon and breast cancer risk.

ABSTRACT: BACKGROUND:Gene amplification leading to overexpression is a common event in breast tumors that is linked to tumor development and progression. The 17q23 region is amplified in >40% of breast tumors and contains several candidate oncogenes. Because common genetic variation in several oncogenes has been associated with cancer risk, we assessed the relevance of common variants in the 17q23 candidate oncogenes to breast cancer. METHODS:We investigated 60 polymorphisms in the TUBD1, SEPT4, PRKCA, TBX2, TBX4, TEX14, TLK2, YPEL2, and PPM1E genes from this amplicon for association with breast cancer risk among 798 Caucasian breast cancer cases and 843 unaffected Caucasian controls from the Mayo Clinic. RESULTS:Eight polymorphisms in PRKCA, TBX4, TLK2, and YPEL2 displayed significant dose-response associations with breast cancer risk (P(trend) < 0.05). Of these, PRKCA rs7342847 and TLK2 rs2245092 and rs733025 were also associated with hormone receptor-positive breast cancer: PRKCA rs7342847 (odds ratio, 0.7; 95% confidence interval, 0.6-0.9; P(trend) = 0.002) and TLK2 rs733025 and rs2245092 (both: odds ratio, 0.8; 95% confidence interval, 0.7-1.0; P(trend) = 0.03). Interactions between SEPT4 rs758377 and TEX14 rs302864 (P(interaction) = 0.0003) and between TLK2 rs733025 and YPEL2 rs16943468 (P(interaction) = 0.05) for risk of breast cancer were also observed. CONCLUSION:These findings suggest that single polymorphisms and combinations of polymorphisms within candidate oncogenes from the 17q23 amplicon may influence risk of breast cancer overall and possibly specific molecular subtypes of breast tumors. The findings are discussed within the context of the results from two independent data sets.

SUBMITTER: Kelemen LE

PROVIDER: S-EPMC2729317 | biostudies-literature | 2009 Jun

REPOSITORIES: biostudies-literature

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Genetic variation in the chromosome 17q23 amplicon and breast cancer risk.

Kelemen Linda E LE Wang Xianshu X Fredericksen Zachary S ZS Pankratz V Shane VS Pharoah Paul D P PD Ahmed Shahana S Dunning Alison M AM Easton Douglas F DF Vierkant Robert A RA Cerhan James R JR Goode Ellen L EL Olson Janet E JE Couch Fergus J FJ

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 20090519 6

<h4>Background</h4>Gene amplification leading to overexpression is a common event in breast tumors that is linked to tumor development and progression. The 17q23 region is amplified in >40% of breast tumors and contains several candidate oncogenes. Because common genetic variation in several oncogenes has been associated with cancer risk, we assessed the relevance of common variants in the 17q23 candidate oncogenes to breast cancer.<h4>Methods</h4>We investigated 60 polymorphisms in the TUBD1, S ...[more]

PMID: 19454617

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Project description:Amplification of chromosome 17q23 is a frequent genomic event that occurs in ~ 11% of human breast cancers. The 17q23 amplification is enriched in HER2+ breast cancers, which is significantly correlated with poor clinical outcomes. Previous studies have identified the oncogenic phosphatase WIP1 gene in the amplicon, which functions as a master inhibitor in DNA damage response. While the possibility of any other protein-coding oncogenes in the WIP1-containing 17q23 amplicon was ruled out, our analysis of human breast cancer genomics uncovered an oncogenic microRNA gene, MIR21, in a majority of the WIP1-containing amplicons. Interestingly, DEAD-box helicase 5 (DDX5), co-amplified with WIP1 and MIR21 in the 17q23 amplicon, facilitates the essential processing of primary miR-21 transcripts. Accordingly, the 17q23 amplification results in aberrant expression of WIP1 and miR-21, which not only promotes breast tumorigenesis, but also leads to resistance to anti-HER2 therapies. Inhibiting WIP1 and miR-21 using small molecular inhibitor against WIP1 (GSK2830371) and anti-miR-21 oligonucleotides selectively inhibits the proliferation, survival and tumorigenic potential of HER2+ breast cancer cells harboring 17q23 amplification. However, the in vivo bioavailability of the two agents in their free form is poor. To overcome the resistance of trastuzumab-based therapies in vivo, we developed pH-sensitive nanoparticles for specific co-delivery of the two agents into breast tumors. The nanoparticles consist of four materials approved by the Food and Drug Administration (FDA) for medical use: Poly (d,l-lactide-co-glycolide) (PLGA), Pluronic F127 (PF127), chitosan, and 1,2-dipalmitoyl-sn-glycerol-3-phosphocholine (DPPC). Moreover, chitosan was modified with guanidine to form chitosan-guanidine (CG), which not only can improve the encapsulation efficiency of anti-miR-21 oligonucleotides but also effectively capture carbon dioxide (CO2) into the nanoparticle to achieve the ‘nano-bomb’ effect for triggered drug release under the reduced pH in tumors. The two agents (inhibitors of miR-21 and WIP1)-laden nanoparticles can be used to efficiently kill trastuzumab-resistant HER2+ breast cancer cells, leading to a profound reduction of the tumor growth in vivo. These results demonstrate the great potential of the combined treatment of WIP1 and miR-21 inhibitors for the HER2+ breast cancers resistant to anti-HER2-based therapies.

Dataset Information

Genetic variation in the chromosome 17q23 amplicon and breast cancer risk.

Publications

Genetic variation in the chromosome 17q23 amplicon and breast cancer risk.

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