ATP7B is a differentially expressed gene in brain metastatic human breast cancer.

Metastasis to the brain is a clinical problem in patients with breast cancer (1-3). We mined published microarray data (4, 5) to compare primary and metastatic tumor transcriptomes for the discovery of genes associated with brain metastasis in humans with metastatic breast cancer. We found that the ATPase copper transporting beta, also known as Wilson disease protein, encoded by ATP7B, was among the genes whose expression was most different in the brain metastases of patients with metastatic breast cancer as compared to primary tumors of the breast. ATP7B mRNA was present at increased quantities in brain metastatic tissues as compared to primary tumors of the breast. Expression of ATP7B in primary tumors was significantly correlated with patient overall survival. Modulation of ATP7B expression may be relevant to the biology by which tumor cells metastasize from the breast to the brain in humans with metastatic breast cancer.

Retromer retrieves the Wilson disease protein ATP7B from endolysosomes in a copper-dependent manner

ABSTRACTThe Wilson disease protein, ATP7B maintains copper (herein referring to the Cu+ ion) homeostasis in the liver. ATP7B traffics from trans-Golgi network to endolysosomes to export excess copper. Regulation of ATP7B trafficking to and from endolysosomes is not well understood. We investigated the fate of ATP7B after copper export. At high copper levels, ATP7B traffics primarily to acidic, active hydrolase (cathepsin-B)-positive endolysosomes and, upon subsequent copper chelation, returns to the trans-Golgi network (TGN). At high copper, ATP7B colocalizes with endolysosomal markers and with a core member of retromer complex, VPS35. Knocking down VPS35 did not abrogate the copper export function of ATP7B or its copper-responsive anterograde trafficking to vesicles; rather upon subsequent copper chelation, ATP7B failed to relocalize to the TGN, which was rescued by overexpressing wild-type VPS35. Overexpressing mutants of the retromer complex-associated proteins Rab7A and COMMD1 yielded a similar non-recycling phenotype of ATP7B. At high copper, VPS35 and ATP7B are juxtaposed on the same endolysosome and form a large complex that is stabilized by in vivo photoamino acid labeling and UV-crosslinking. We demonstrate that retromer regulates endolysosome to TGN trafficking of copper transporter ATP7B in a manner that is dependent upon intracellular copper.

Copper relay path through the N-terminus of Wilson disease protein, ATP7B

Using a yeast assay, we identified the roles of ATP7B's six metal-binding domains in internal copper transport and soluble chaperone capacity.

A glimpse into the regulation of the Wilson disease protein, ATP7B, sheds light on the complexity of mammalian apical trafficking pathways

Wilson disease (WD), a Mendelian disorder of copper metabolism caused by mutations in the ATP7B gene, manifests a large spectrum of phenotypic variability.

Probing functional roles of Wilson disease protein (ATP7B) copper-binding domains in yeast

A double deleted yeast system was developed to probe activity of human ATP7B variants in the presence of human Atox1.