Association of NCOA3 Polymorphisms with Breast Cancer Risk

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.

[1]  Adrian V. Lee,et al.  AIB1/SRC-3 Deficiency Affects Insulin-Like Growth Factor I Signaling Pathway and Suppresses v-Ha-ras-induced Breast Cancer Initiation and Progression in Mice , 2004, Cancer Research.

[2]  S. Karlin,et al.  What drives codon choices in human genes? , 1996, Journal of molecular biology.

[3]  K. Czene,et al.  Attributable risks for familial breast cancer by proband status and morphology: A nationwide epidemiologic study from Sweden , 2002, International journal of cancer.

[4]  C. Davio,et al.  Hormone dependence of mammary tumors induced in rats by intraperitoneal NMU injection. , 1997, Cancer investigation.

[5]  K. Hemminki,et al.  Polyglutamine repeat length in the NCOA3 does not affect risk in familial breast cancer. , 2005, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[6]  Nazneen Rahman,et al.  Low-penetrance susceptibility to breast cancer due to CHEK2*1100delC in noncarriers of BRCA1 or BRCA2 mutations , 2002, Nature Genetics.

[7]  A. Howell,et al.  New approaches to the endocrine prevention and treatment of breast cancer , 2003, Cancer Chemotherapy and Pharmacology.

[8]  D. Parkin,et al.  Epidemiology of cancer: global patterns and trends. , 1998, Toxicology letters.

[9]  A. Wellstein,et al.  An Isoform of the Coactivator AIB1 That Increases Hormone and Growth Factor Sensitivity Is Overexpressed in Breast Cancer* , 2001, The Journal of Biological Chemistry.

[10]  P. Meltzer,et al.  AIB1, a steroid receptor coactivator amplified in breast and ovarian cancer. , 1997, Science.

[11]  C. Powers,et al.  Ribozyme Targeting Demonstrates That the Nuclear Receptor Coactivator AIB1 Is a Rate-limiting Factor for Estrogen-dependent Growth of Human MCF-7 Breast Cancer Cells* , 2001, The Journal of Biological Chemistry.

[12]  A. Meindl,et al.  Comprehensive analysis of 989 patients with breast or ovarian cancer provides BRCA1 and BRCA2 mutation profiles and frequencies for the German population , 2002, International journal of cancer.

[13]  M. Osborne,et al.  The Role of Estrogen in Mammary Carcinogenesis a , 1995, Annals of the New York Academy of Sciences.

[14]  R. Lanz,et al.  RAC‐3 is a NF‐κB coactivator , 2000 .

[15]  W. Willett,et al.  Polymorphic repeat in AIB1 does not alter breast cancer risk , 2000, Breast Cancer Research.

[16]  P. Meltzer,et al.  Specific chromosomal aberrations and amplification of the AIB1 nuclear receptor coactivator gene in pancreatic carcinomas. , 1999, The American journal of pathology.

[17]  N. Saitou,et al.  Synonymous mutations in the human dopamine receptor D2 (DRD2) affect mRNA stability and synthesis of the receptor. , 2003, Human molecular genetics.

[18]  D. Easton,et al.  EMGM Abstracts , 2003, Genetic epidemiology.

[19]  P. Kantoff,et al.  Modification of BRCA1- and BRCA2-associated breast cancer risk by AIB1 genotype and reproductive history. , 2001, Cancer research.

[20]  K. Hemminki,et al.  Sex hormone-binding globulin polymorphisms in familial and sporadic breast cancer. , 2002, Carcinogenesis.

[21]  Yusuke Nakamura,et al.  Amplification and over‐expression of the AIB1 nuclear receptor co‐activator gene in primary gastric cancers , 2000, International journal of cancer.

[22]  J. Gray,et al.  The genetics and genomics of cancer , 2003, Nature Genetics.

[23]  J. Qin,et al.  Regulation of SRC-3 (pCIP/ACTR/AIB-1/RAC-3/TRAM-1) Coactivator Activity by IκB Kinase , 2002, Molecular and Cellular Biology.

[24]  H. Akashi,et al.  Gene expression and molecular evolution. , 2001, Current opinion in genetics & development.

[25]  J. Peto,et al.  The future of association studies of common cancers , 2003, Human Genetics.

[26]  R. Evans,et al.  Nuclear Receptor Coactivator ACTR Is a Novel Histone Acetyltransferase and Forms a Multimeric Activation Complex with P/CAF and CBP/p300 , 1997, Cell.

[27]  Simak Ali,et al.  Endocrine-responsive breast cancer and strategies for combating resistance , 2002, Nature Reviews Cancer.

[28]  M. Louie,et al.  ACTR/AIB1 Functions as an E2F1 Coactivator To Promote Breast Cancer Cell Proliferation and Antiestrogen Resistance , 2004, Molecular and Cellular Biology.

[29]  A. Wellstein,et al.  Impact of the nuclear receptor coactivator AIB1 isoform AIB1-Δ3 on estrogenic ligands with different intrinsic activity , 2004, Oncogene.

[30]  Han-Jong Kim,et al.  Steroid receptor coactivator-1 and its family members differentially regulate transactivation by the tumor suppressor protein p53. , 1999, Molecular endocrinology.

[31]  R. Eeles,et al.  Polyglutamine repeat length in the AIB1 gene modifies breast cancer susceptibility in BRCA1 carriers , 2004, International journal of cancer.

[32]  S. Hilsenbeck,et al.  Role of the estrogen receptor coactivator AIB1 (SRC-3) and HER-2/neu in tamoxifen resistance in breast cancer. , 2003, Journal of the National Cancer Institute.

[33]  R. Schiff,et al.  Mechanisms of tamoxifen resistance: increased estrogen receptor-HER2/neu cross-talk in ER/HER2-positive breast cancer. , 2004, Journal of the National Cancer Institute.

[34]  P. Meltzer,et al.  In breast cancer, amplification of the steroid receptor coactivator gene AIB1 is correlated with estrogen and progesterone receptor positivity. , 1998, Clinical cancer research : an official journal of the American Association for Cancer Research.

[35]  X. Guan,et al.  Prognostic significance of c‐myc and AIB1 amplification in hepatocellular carcinoma , 2002, Cancer.

[36]  Ralf Janknecht,et al.  Concerted Activation of ETS Protein ER81 by p160 Coactivators, the Acetyltransferase p300 and the Receptor Tyrosine Kinase HER2/Neu* , 2004, Journal of Biological Chemistry.

[37]  X. Xia.  Maximizing transcription efficiency causes codon usage bias. , 1996, Genetics.

[38]  M. Southey,et al.  Overexpression of the steroid receptor coactivator AIB1 in breast cancer correlates with the absence of estrogen and progesterone receptors and positivity for p53 and HER2/neu. , 2001, Cancer research.

[39]  R. Evans,et al.  Regulation of Hormone-Induced Histone Hyperacetylation and Gene Activation via Acetylation of an Acetylase , 1999, Cell.