title: PMCA2 regulates HER2 protein kinase localization and signaling and promotes HER2-mediated breast cancer.
abstract: In the lactating mammary gland, the plasma membrane calcium ATPase2 (PMCA2) transports milk calcium. Its expression is activated in breast cancers, where high tumor levels predict increased mortality. We find that PMCA2 expression correlates with HER2 levels in breast cancers and that PMCA2 interacts with HER2 in specific actin-rich membrane domains. Knocking down PMCA2 increases intracellular calcium, disrupts interactions between HER2 and HSP-90, inhibits HER2 signaling, and results in internalization and degradation of HER2. Manipulating PMCA2 levels regulates the growth of breast cancer cells, and knocking out PMCA2 inhibits the formation of tumors in mouse mammary tumor virus (MMTV)-Neu mice. These data reveal previously unappreciated molecular interactions regulating HER2 localization, membrane retention, and signaling, as well as the ability of HER2 to generate breast tumors, suggesting that interactions between PMCA2 and HER2 may represent therapeutic targets for breast cancer.
authors.affiliation: Section of Endocrinology and Metabolism, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520;
authors.forename: Jaekwang
authors.initials: J
authors.lastname: Jeong
authors.affiliation: Section of Endocrinology and Metabolism, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520;
authors.forename: Joshua N
authors.initials: JN
authors.lastname: VanHouten
authors.affiliation: Section of Endocrinology and Metabolism, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520;
authors.forename: Pamela
authors.initials: P
authors.lastname: Dann
authors.affiliation: Section of Endocrinology and Metabolism, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520;
authors.forename: Wonnam
authors.initials: W
authors.lastname: Kim
authors.affiliation: Department of Pediatrics, Yale University School of Medicine, New Haven, CT 06520;
authors.forename: Catherine
authors.initials: C
authors.lastname: Sullivan
authors.affiliation: Cancer Epidemiology Program, University of Hawaii Cancer Center, University of Hawaii School of Medicine, Honolulu, HI 96813;
authors.forename: Herbert
authors.initials: H
authors.lastname: Yu
authors.affiliation: Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA 20110;
authors.forename: Lance
authors.initials: L
authors.lastname: Liotta
authors.affiliation: Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA 20110;
authors.forename: Virginia
authors.initials: V
authors.lastname: Espina
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, CT 06520;
authors.forename: David F
authors.initials: DF
authors.lastname: Stern
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Friedman
authors.affiliation: Section of Endocrinology and Metabolism, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520; John.Wysolmerski@yale.edu.
authors.forename: John J
authors.initials: JJ
authors.lastname: Wysolmerski
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D002118:Calcium / Q000494:pharmacology; D063646:Carcinogenesis / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D049109:Cell Proliferation; D002470:Cell Survival; D004705:Endocytosis / Q000187:drug effects; D005260:Female; D005455:Fluorescent Antibody Technique; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism; D055785:Gene Knockdown Techniques; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D042541:Intracellular Space / Q000378:metabolism; D015674:Mammary Neoplasms, Animal; D051379:Mice; D053499:Plasma Membrane Calcium-Transporting ATPases / Q000378:metabolism*; D011485:Protein Binding; D021381:Protein Transport; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D016019:Survival Analysis
chemical_list: D002118:Calcium; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D018841:HSP90 Heat-Shock Proteins; D053499:Plasma Membrane Calcium-Transporting ATPases; D018719:Erb-b2 Receptor Tyrosine Kinases; C085126:FOXO1 protein, human; C508053:ERBB2 protein, human; C506958:ATP2B2 protein, human; C506959:Atp2b2 protein, mouse
keywords: ErbB2; HSP-90; calcium pumps; epidermal growth factor receptor; receptor internalization