Breast cancer is the most frequently diagnosed
cancer among women in western countries and bone
metastases of
breast cancer cause significant morbidity.
G proteins are important components of a multitude of transmembrane receptors and are involved in the regulation of intracellular signaling pathways such as
parathormone receptors 1 and 2 (PTH1 and 2), extracellular
calcium-sensing receptor, the
calcitonin receptor and the OPG/RANKL-system. A common polymorphism in the gene encoding the
G protein beta3-subunit, GNB3 825C > T, has been linked to increased
G protein activation. To analyse the role of this polymorphism in bone
metastasis of
breast cancer, we determined GNB3 825C > T genotypes in 500 female
breast cancer patients. According to
breast cancer staging, patients were divided in three groups, representing patients without
metastases (n = 250), those with
metastases other than bone (n = 117), and those with bone
metastasis (n = 133). Frequency of the GNB3 825 TT genotype was significantly lower among patients with bone
metastases (3.1%) than among those with other
metastases (12.8%; P = 0.004) or no
metastases (13.3%; P < 0.001). In a Cox regression analysis, relative risk of the GNB3 TT genotype for bone
metastasis was 0.22 (95% CI 0.08-0.61; P = 0.004) for bone
metastasis. We conclude that the homozygous GNB3 825 TT genotype may be protective against development of bone
metastasis in
breast cancer patients. The precise mechanism for this remains to be determined, but could be due to a direct involvement of
G protein-coupled receptors in bone metabolism.