title: Clinical significance of glycoprotein nonmetastatic B and its association with HER2 in breast cancer.
abstract: Glycoprotein nonmetastatic B (GPNMB) is a potential oncogene that is particularly expressed in melanoma and breast cancer (BC). To clarify its clinical significance in BC, we measured serum GPNMB in vivo and investigated its cross talk with human epidermal growth factor 2 (HER2). GPNMB was expressed in four of six breast cell lines (SK-BR-3, BT-474, MDA-MD-231, and MDA-MD-157), two of six colorectal cell lines, and two of four gastric cancer (GC) cell lines. We established a GPNMB quantification system using enzyme-linked immunosorbent assay (ELISA) for these cell lines. We measured serum GPNMB in vivo in 162 consecutive BC patients and in 88 controls (50 colorectal cancer [CC] and 38 GC patients). The GPNMB concentration in BC, CC and GC was 8.163, 5.751 and 6.55 ng/mL, respectively. The GPNMB level was significantly higher in BC patients than in CC patients (P = 0.021). The HER2-rich subtype of BC patients had significantly higher GPNMB levels than other subtypes (vs. Luminal; P = 0.038; vs. DCIS; P = 0.0195). These high GPNMB levels decreased after treatment (surgery/chemotherapy). Next, we examined the relationship between GPNMB and HER2 in vitro using SK-BR3 and BT-474 (HER2-positive/GPNMB-positive) cells. GPNMB depletion by small interfering RNA (siRNA) increased both HER2 expression and phosphorylation. Trastuzumab (Tra) in combination with docetaxel promoted cell growth inhibition, and treatment with Tra or an Extracellular signal-related kinase (ERK) inhibitor enhanced GPNMB expression. These results indicate that GPNMB might be a surrogate marker for BC and may cross talk with the HER2 signal pathway. GPNMB may therefore emerge as an important player in anti-HER2 therapy.
authors.affiliation: Department of Surgical Oncology, Graduate School of Medicine, Gifu University, Gifu, Japan.
authors.forename: Masako
authors.initials: M
authors.lastname: Kanematsu
authors.affiliation: Department of Breast and Molecular Oncology, Graduate School of Medicine, Gifu University, Gifu, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Futamura
authors.affiliation: Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, Japan.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Takata
authors.affiliation: Department of Surgical Oncology, Graduate School of Medicine, Gifu University, Gifu, Japan.
authors.forename: Siqin
authors.initials: S
authors.lastname: Gaowa
authors.affiliation: Department of Surgical Oncology, Graduate School of Medicine, Gifu University, Gifu, Japan.
authors.forename: Atsuko
authors.initials: A
authors.lastname: Yamada
authors.affiliation: Department of Breast and Molecular Oncology, Graduate School of Medicine, Gifu University, Gifu, Japan.
authors.forename: Kasumi
authors.initials: K
authors.lastname: Morimitsu
authors.affiliation: Department of Surgical Oncology, Graduate School of Medicine, Gifu University, Gifu, Japan.
authors.forename: Akemi
authors.initials: A
authors.lastname: Morikawa
authors.affiliation: Department of Surgical Oncology, Graduate School of Medicine, Gifu University, Gifu, Japan.
authors.forename: Ryutaro
authors.initials: R
authors.lastname: Mori
authors.affiliation: Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Hara
authors.affiliation: Department of Surgical Oncology, Graduate School of Medicine, Gifu University, Gifu, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Yoshida
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000628:therapy; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D015870:Gene Expression; D006801:Humans; D008562:Membrane Glycoproteins / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D011485:Protein Binding; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D008562:Membrane Glycoproteins; D034741:RNA, Small Interfering; D018719:Erb-b2 Receptor Tyrosine Kinases; C503042:GPNMB protein, human
keywords: Biomarker; GPNMB; HER2; breast cancer; cross talk