Skip Navigation



Carcinogenesis Advance Access published online on September 6, 2006
Carcinogenesis, doi:10.1093/carcin/bgl164
This Article
Right arrow Advance Access manuscript (PDF) Freely available
Right arrow All Versions of this Article:
28/2/423    most recent
bgl164v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Wirtenberger, M.
Right arrow Articles by Burwinkel, B.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Wirtenberger, M.
Right arrow Articles by Burwinkel, B.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The Author 2006. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org
Received June 14, 2006
Revised August 11, 2006
Accepted August 24, 2006

MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION

The functional genetic variant Ile646Val located in the kinase binding domain of the A kinase anchoring protein 10 is associated with familial breast cancer

Michael Wirtenberger 1 * *, Julia Schmutzhard 1 *, Kari Hemminki 2, Alfons Meindl 3, Christian Sutter 4, Rita K. Schmutzler 5, Barbara Wappenschmidt 5, Marion Kiechle 3, Norbert Arnold 6, Bernhard H. F. Weber 7, Dieter Niederacher 8, Claus R. Bartram 4, and Barbara Burwinkel 9

1 Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany; Helmholtz-University Group Molecular Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
2 Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Biosciences at Novum, Karolinska Institute, Huddinge, Sweden
3 Department of Gynaecology and Obstetrics, Klinikum rechts der Isar at the Technical University, Munich, Germany
4 Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany
5 Division of Molecular Gynaeco-Oncology, Department of Gynaecology and Obstetrics, Center of Molecular Medicine Cologne (CMMC), University Hospital of Cologne, Germany
6 Division of Oncology, Department of Gynaecology and Obstetrics, University Hospital Schleswig-Holstein, Kiel, Germany
7 Institute of Human Genetics, University of Regensburg, Regensburg, Germany
8 Division of Molecular Genetics, Department of Gynaecology and Obstetrics, Clinical Center University of Düsseldorf, Düsseldorf, Germany
9 Division of Molecular Genetic Epidemiology, German; Helmholtz-University Group Molecular Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany

* To whom correspondence should be addressed.
Michael Wirtenberger, E-mail: m.wirtenberger{at}dkfz.de


  Abstract

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 localising 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 (OR = 1.25, 95 % 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 {alpha} by PKA induces resistance against the antiestrogen 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 localisation of PKA, it will be interesting to investigate whether this polymorphism influences the effectiveness of PKA and tamoxifen based therapeutic anticancer concepts.

*The first two authors contributed equally to this work
Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 JNCI J Natl Cancer InstHome page
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]

Home page
 Proc. Natl. Acad. Sci. USAHome page
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]


Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.