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

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 Ile 646 Val, located in the kinase-binding domain of AKAP10, is a low-penetrance familial breast cancer risk factor. Ile 646 Val 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 Ile 646 Val 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 Lys 526 Gln is associated with familial breast cancer (OR = 1.58). Here, we discovered that carriers of both variants, AKAP10 Ile 646 Val and AKAP13 Lys 526 Gln, 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) α by PKA induces resistance against the anti-estrogen tamoxifen. Our results indicate for the first time the importance of AKAP10 Ile 646 Val for familial breast cancer susceptibility. Due to the impact of Ile 646 Val 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.