Clinical significance of glycoprotein nonmetastatic B and its association with HER2 in breast cancer.
Clinical significance of glycoprotein nonmetastatic B and its association with HER2 in breast cancer.
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DOI：
10.1002/cam4.480
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发表时间：
2015-09
期刊：
影响因子：
4
通讯作者：
Yoshida K
中科院分区：
文献类型：
--
作者：
Kanematsu M;Futamura M;Takata M;Gaowa S;Yamada A;Morimitsu K;Morikawa A;Mori R;Hara H;Yoshida K
非转移性糖蛋白B（GPNMB）是一种潜在的癌基因，特别是在黑色素瘤和乳腺癌（BC）中表达。为了阐明其在BC中的临床意义，我们测量了体内血清GPNMB并研究了其与人表皮生长因子2（HER 2）的串扰。GPNMB在六种乳腺细胞系中的四种（SK-BR-3、BT-474、MDA-MD-231和MDA-MD-157）、六种结肠直肠细胞系中的两种和四种胃癌（GC）细胞系中的两种中表达。我们建立了一个GPNMB定量系统，使用酶联免疫吸附测定（ELISA）的这些细胞系。我们测量了162例连续BC患者和88例对照（50例结直肠癌[CC]和38例GC患者）的血清GPNMB。BC、CC和GC中的GPNMB浓度分别为8.163、5.751和6.55 ng/mL。BC组GPNMB水平显著高于CC组（P = 0.021）。BC患者的富HER 2亚型的GPNMB水平显著高于其他亚型（vs. Luminal; P = 0.038; vs. DCIS; P = 0.0195）。这些高GPNMB水平在治疗（手术/化疗）后降低。接下来，我们使用SK-BR 3和BT-474（HER 2阳性/GPNMB阳性）细胞在体外检查GPNMB和HER 2之间的关系。通过小干扰RNA（siRNA）消耗GPNMB增加HER 2表达和磷酸化。曲妥珠单抗（Tra）联合多西他赛促进细胞生长抑制，Tra或细胞外信号相关激酶（ERK）抑制剂处理增强GPNMB表达。这些结果表明，GPNMB可能是BC的替代标志物，并可能与HER 2信号通路交叉。因此，GPNMB可能成为抗HER 2治疗的重要参与者。
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.