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Association of NCOA3 Polymorphisms with Breast Cancer Risk

¹ Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ); ² Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany; ³ Department of Molecular Gynaeco-Oncology, Division of Gynaecology and Obstetrics, Clinical Center University of Cologne, Cologne, Germany; ⁴ Department of Tumor Biology, Center of Oncology, Maria Sklodowska-Curie Institute, Gliwice, Poland; ⁵ Department of Genetic Toxicology, Institute of Occupational Medicine and Environmental Health, Sosnowiec, Poland; ⁶ Institute of Transfusion Medicine and Immunology, Red Cross Blood Service of Baden-Württemberg—Hessia, Faculty of Clinical Medicine, University of Heidelberg, Mannheim, Germany; and ⁷ Karolinska Institute, Department at Biosciences at Novum, Huddinge, Sweden

Requests for reprints: Barbara Burwinkel, Division of Molecular Genetic Epidemiology C050, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120 Heidelberg, Germany. Phone: 49-6221-421802; Fax: 49-6221-421810; E-mail: b.burwinkel{at}dkfz.de.

The nuclear receptor coactivator 3 (NCOA3, also known as AIB1) is a coactivator of nuclear receptors like the estrogen receptor. NCOA3 is overexpressed in 60% of primary human breast tumors, and high levels of NCOA3 expression are associated with tamoxifen resistance and worse survival rate. In contrast, NCOA3 deficiency suppresses v-Ha-ras–induced breast cancer initiation and progression in mice. Here, we analyzed the influence of NCOA3 coding single nucleotide polymorphisms on breast cancer risk by performing a case-control study using a German and a Polish study population and identified an association between NCOA3 polymorphisms and breast cancer. A joint analysis of the German and the Polish study population revealed a significant protective effect for the 1758G>C (Q586H) and 2880A>G (T960T) variants. In addition, haplotype analysis showed a protective effect of the 1758C-2880A and 1758G-2880G haplotypes (odds ratio 0.79; 95% confidence interval, 0.67-0.93; P = 0.004). Because of the impact of NCOA3 in antiestrogen therapy resistance, these polymorphisms might also influence therapy outcome in breast cancer.

Key Words: Breast cancer • Carcinogenesis • Cancer susceptibility genes • Therapy outcome • Estrogen

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