Carcinogenesis Advance Access originally published online on September 6, 2006
Carcinogenesis 2007 28(2):423-426; doi:10.1093/carcin/bgl164
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
The functional genetic variant Ile646Val located in the kinase binding domain of the A-kinase anchoring protein 10 is associated with familial breast cancer
1 Division of Molecular Genetic Epidemiology Heidelberg, Germany
2 Helmholtz-University Group Molecular Epidemiology, German Cancer Research Center (DKFZ) Heidelberg, Germany
3 Department of Biosciences at Novum, Karolinska Institute Huddinge, Sweden
4 Department of Gynaecology and Obstetrics, Klinikum rechts der Isar at the Technical University Munich
5 Institute of Human Genetics, University of Heidelberg Heidelberg
6 Division of Molecular Gynaeco-Oncology, Department of Gynaecology and Obstetrics Center of Molecular Medicine Cologne (CMMC), University Hospital of Cologne
7 Division of Oncology, Department of Gynaecology and Obstetrics University Hospital Schleswig-Holstein, Kiel
8 Institute of Human Genetics, University of Regensburg Regensburg
9 Division of Molecular Genetics, Department of Gynaecology and Obstetrics Clinical Center University of Düsseldorf, Düsseldorf, Germany
*To whom correspondence should be addressed at: Division of Molecular Genetic Epidemiology C050, German Cancer Research Centre (DKFZ), Im Neuenheimer Feld 580, 69120 Heidelberg, Germany. Tel: +49 6221 421811; Fax: +49 6221 421810; Email: m.wirtenberger{at}dkfz.de
Overexpression of cAMP-dependent protein kinase A (PKA) is a hallmark of the great majority of human cancers including breast cancer. A-kinase anchoring proteins (AKAPs) coordinate the specificity of PKA signalling by localizing the kinase to its subcellular sites. We tested the hypothesis whether the functional amino acid exchange Ile646Val, located in the kinase-binding domain of AKAP10, is a low-penetrance familial breast cancer risk factor. Ile646Val alters the binding of AKAP10 to PKA and is associated with morbidity. The analysis of 787 BRCA1/2 mutation-negative familial breast cancer patients and 993 controls revealed an association of the AKAP10 Ile646Val polymorphism with increased familial breast cancer risk [odds ratio (OR) = 1.25, 95% confidence interval (CI) 1.03–1.51, P = 0.024]. Our previous study has shown that AKAP13 Lys526Gln is associated with familial breast cancer (OR = 1.58). Here, we discovered that carriers of both variants, AKAP10 Ile646Val and AKAP13 Lys526Gln, are at a further enhanced breast cancer risk (OR = 2.41, 95% CI 1.30–4.46, P = 0.005). PKA is a major target of therapeutic anticancer strategies. Phosphorylation of the estrogen receptor (ER) 
by PKA induces resistance against the anti-estrogen tamoxifen. Our results indicate for the first time the importance of AKAP10 Ile646Val for familial breast cancer susceptibility. Due to the impact of Ile646Val on the subcellular localization of PKA, it will be interesting to investigate whether this polymorphism influences the effectiveness of PKA and tamoxifen based therapeutic anticancer concepts.
Abbreviations: PKA, protein kinase A; AKAPs, A-kinase-anchoring proteins; ER, estrogen receptor; ORs, odds ratios; CI, confidence interval
The first two authors contributed equally to this work. Received June 14, 2006; revised August 11, 2006; accepted August 24, 2006.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  C. T. Eggers, J. C. Schafer, J. R. Goldenring, and S. S. Taylor D-AKAP2 Interacts with Rab4 and Rab11 through Its RGS Domains and Regulates Transferrin Receptor Recycling J. Biol. Chem., November 20, 2009; 284(47): 32869 - 32880. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Frank, M. Wiestler, S. Kropp, K. Hemminki, A. B. Spurdle, C. Sutter, B. Wappenschmidt, X. Chen, J. Beesley, J. L. Hopper, et al. Association of a Common AKAP9 Variant With Breast Cancer Risk: A Collaborative Analysis J Natl Cancer Inst, March 19, 2008; 100(6): 437 - 442. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. G. Tingley, L. Pawlikowska, J. G. Zaroff, T. Kim, T. Nguyen, S. G. Young, K. Vranizan, P.-Y. Kwok, M. A. Whooley, and B. R. Conklin Gene-trapped mouse embryonic stem cell-derived cardiac myocytes and human genetics implicate AKAP10 in heart rhythm regulation PNAS, May 15, 2007; 104(20): 8461 - 8466. [Abstract] [Full Text] [PDF]
|
|