Bone
metastasis is the most common distant relapse in
breast cancer. The identification of key
proteins involved in the osteotropic phenotype would represent a major step toward the development of new prognostic markers and therapeutic improvements. The aim of this study was to characterize functional phenotypes that favor bone
metastasis in human
breast cancer. We used the human
breast cancer cell line MDA-MB-231 and its osteotropic
BO2 subclone to identify crucial
proteins in bone metastatic growth. We identified 31
proteins, 15 underexpressed and 16 overexpressed, in
BO2 cells compared with parental cells. We employed a network-modeling approach in which these 31 candidate
proteins were prioritized with respect to their potential in
metastasis formation, based on the topology of the protein-protein interaction network and differential expression. The protein-protein interaction network provided a framework to study the functional relationships between
biological molecules by attributing functions to genes whose functions had not been characterized. The combination of expression profiles and
protein interactions revealed an endoplasmic reticulum-
thiol oxidoreductase, ERp57, functioning as a hub that retained four down-regulated nodes involved in antigen presentation associated with the human major histocompatibility complex class I molecules, including
HLA-A,
HLA-B, HLA-E, and HLA-F. Further analysis of the interaction network revealed an inverse correlation between ERp57 and
vimentin, which influences cytoskeleton reorganization. Moreover, knockdown of ERp57 in
BO2 cells confirmed its bone organ-specific prometastatic role. Altogether, ERp57 appears as a multifunctional chaperone that can regulate diverse biological processes to maintain the homeostasis of
breast cancer cells and promote the development of bone
metastasis.