title: The functional genetic variant Ile646Val located in the kinase binding domain of the A-kinase anchoring protein 10 is associated with familial breast cancer.
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 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) alpha 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.
authors.affiliation: Division of Molecular Genetic Epidemiology, Helmholtz-University Group Molecular Epidemiology, German Cancer Research Center, Heidelberg, and Department of Gynaecology and Obstetrics, University Hospital of Cologne, Germany. m.wirtenberger@dkfz.de
authors.forename: Michael
authors.initials: M
authors.lastname: Wirtenberger
authors.forename: Julia
authors.initials: J
authors.lastname: Schmutzhard
authors.forename: Kari
authors.initials: K
authors.lastname: Hemminki
authors.forename: Alfons
authors.initials: A
authors.lastname: Meindl
authors.forename: Christian
authors.initials: C
authors.lastname: Sutter
authors.forename: Rita K
authors.initials: RK
authors.lastname: Schmutzler
authors.forename: Barbara
authors.initials: B
authors.lastname: Wappenschmidt
authors.forename: Marion
authors.initials: M
authors.lastname: Kiechle
authors.forename: Norbert
authors.initials: N
authors.lastname: Arnold
authors.forename: Bernhard H F
authors.initials: BH
authors.lastname: Weber
authors.forename: Dieter
authors.initials: D
authors.lastname: Niederacher
authors.forename: Claus R
authors.initials: CR
authors.lastname: Bartram
authors.forename: Barbara
authors.initials: B
authors.lastname: Burwinkel
mesh_terms: D054758:A Kinase Anchor Proteins; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics*; D015331:Cohort Studies; D017931:DNA Primers; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D007532:Isoleucine / Q000235:genetics*; D012307:Risk Factors; D014633:Valine / Q000235:genetics*
chemical_list: D054758:A Kinase Anchor Proteins; C484639:AKAP10 protein, human; D048868:Adaptor Proteins, Signal Transducing; D017931:DNA Primers; D007532:Isoleucine; D014633:Valine