Marseille Cancer Research Center, UMR891 Inserm, Institut Paoli-Calmettes, Department of Molecular Oncology, Marseille, France.
BMC Cancer. 2010 Oct 8;10:539. doi: 10.1186/1471-2407-10-539.
Around 20% of breast cancers (BC) show ERBB2 gene amplification and overexpression of the ERBB2 tyrosine kinase receptor. They are associated with a poor prognosis but can benefit from targeted therapy. A better knowledge of these BCs, genomically and biologically heterogeneous, may help understand their behavior and design new therapeutic strategies.
We defined the high resolution genome and gene expression profiles of 54 ERBB2-amplified BCs using 244K oligonucleotide array-comparative genomic hybridization and whole-genome DNA microarrays. Expression of ERBB2, phosphorylated ERBB2, EGFR, IGF1R and FOXA1 proteins was assessed by immunohistochemistry to evaluate the functional ERBB2 status and identify co-expressions.
First, we identified the ERBB2-C17orf37-GRB7 genomic segment as the minimal common 17q12-q21 amplicon, and CRKRS and IKZF3 as the most frequent centromeric and telomeric amplicon borders, respectively. Second, GISTIC analysis identified 17 other genome regions affected by copy number aberration (CNA) (amplifications, gains, losses). The expression of 37 genes of these regions was deregulated. Third, two types of heterogeneity were observed in ERBB2-amplified BCs. The genomic profiles of estrogen receptor-positive (ER+) and negative (ER-) ERBB2-amplified BCs were different. The WNT/β-catenin signaling pathway was involved in ER- ERBB2-amplified BCs, and PVT1 and TRPS1 were candidate oncogenes associated with ER+ ERBB2-amplified BCs. The size of the ERBB2 amplicon was different in inflammatory (IBC) and non-inflammatory BCs. ERBB2-amplified IBCs were characterized by the downregulated and upregulated mRNA expression of ten and two genes in proportion to CNA, respectively. IHC results showed (i) a linear relationship between ERBB2 gene amplification and its gene and protein expressions with a good correlation between ERBB2 expression and phosphorylation status; (ii) a potential signaling cross-talk between EGFR or IGF1R and ERBB2, which could influence response of ERBB2-positive BCs to inhibitors. FOXA1 was frequently coexpressed with ERBB2 but its expression did not impact on the outcome of patients with ERBB2-amplified tumors.
We have shown that ER+ and ER- ERBB2-amplified BCs are different, distinguished ERBB2 amplicons in IBC and non-IBC, and identified genomic features that may be useful in the design of alternative therapeutical strategies.
约 20%的乳腺癌（BC）表现出 ERBB2 基因扩增和 ERBB2 酪氨酸激酶受体的过度表达。它们与预后不良相关，但可受益于靶向治疗。对这些基因组和生物学上异质性的 BC 的更好了解，可能有助于理解它们的行为并设计新的治疗策略。
我们使用 244K 寡核苷酸阵列比较基因组杂交和全基因组 DNA 微阵列定义了 54 个 ERBB2 扩增的 BC 的高分辨率基因组和基因表达谱。通过免疫组织化学评估 ERBB2、磷酸化 ERBB2、EGFR、IGF1R 和 FOXA1 蛋白的表达，以评估功能性 ERBB2 状态并确定共表达。
首先，我们确定了 ERBB2-C17orf37-GRB7 基因组片段作为最小的共同 17q12-q21 扩增子，CRKRS 和 IKZF3 分别为最常见的着丝粒和端粒扩增子边界。其次，GISTIC 分析鉴定出其他 17 个受拷贝数改变（CNA）（扩增、增益、缺失）影响的基因组区域。这些区域的 37 个基因的表达失调。第三，在 ERBB2 扩增的 BC 中观察到两种类型的异质性。雌激素受体阳性（ER+）和阴性（ER-）ERBB2 扩增的 BC 的基因组谱不同。WNT/β-catenin 信号通路参与 ER-ERBB2 扩增的 BC，而 PVT1 和 TRPS1 是与 ER+ERBB2 扩增的 BC 相关的候选癌基因。炎症性（IBC）和非炎症性 BC 中 ERBB2 扩增子的大小不同。ERBB2 扩增的 IBC 特征是与 CNA 成比例的十个和两个基因的 mRNA 表达下调和上调。免疫组化结果显示：（i）ERBB2 基因扩增与其基因和蛋白表达之间存在线性关系，并且 ERBB2 表达与磷酸化状态之间具有良好的相关性；（ii）EGFR 或 IGF1R 与 ERBB2 之间存在潜在的信号转导交叉对话，这可能影响 ERBB2 阳性 BC 对抑制剂的反应。FOXA1 常与 ERBB2 共表达，但表达不影响 ERBB2 扩增肿瘤患者的预后。
我们已经表明，ER+和 ER-ERBB2 扩增的 BC 是不同的，区分了 IBC 和非 IBC 中的 ERBB2 扩增子，并确定了可能有助于设计替代治疗策略的基因组特征。
