King Abdulaziz University, PO BOX 80216, Jeddah 21589, Kingdom of Saudi Arabia. Tel: +966 126401000 ext 25123,
Anticancer Res. 2014 Mar;34(3):1355-66.
BACKGROUND/AIM: Breast cancer (BC) is the most common type of cancer in Saudi women. Matrix metalloproteinases (MMPs) are endopeptidases with the ability to degrade extracellular matrix proteins. In healthy individual tissue disruption is prevented by precised regulation of MMPs; however, in cancer a number of MMPs are overexpressed causing tissue disruption and making tumor cells capable of invasion and metastasis. Invasive ductal carcinoma (IDC) of BCs are classified into grade 1 (G1), grade 2 (G2) and grade 3 (G3) tumors.
We performed a transcriptomic profiling of 38 surgically-resected breast tumors (4 G1, 17 G2 and 17 G3) using Affymetrix Gene 1.0 ST microarrays. Differentially expressed genes for each grade were identified by the Partek Genomic Suite 6.4 and expression analysis results were validated by immunohistochemistry at the protein level. Pathway analyses and establishment of clinical significance of findings were performed using the appropriate software.
We identified 1,593 differentially expressed genes in BC grades in comparison to normal samples using a cut-off of p<0.05 and fold change >2. Out of these genes 429 were expressed throughout in all grades along with tumor progression while many others associated with specific grades (440 genes in G1, 203 in G2 and 394 in G3 only) were exclusively. Microarray results indicate that mRNA expression of MMP-1, -9,-11,-12, and -13 were up-regulated in higher BC grades when compared to normal breast tissues. MMP-9 was expressed in most IDC (97.5%) samples and was highly expressed in 55% of the tumors. Differential expression of MMP-9 significantly correlated with histological BC grades of (p=0.03) and strongly correlated with overall survival (p=0.08).
Gene expression signatures are unique for specific grades. Overexpression of MMPs in higher grades might be associated with BC tumor invasion and metastasis. Therefore, MMPs, and MMP-9 in particular, are reliable candidates for diagnostic biomarker and drug target and further functional analyses have to be performed in order to confirm their role in BC. Our results also suggest the incidence of MMP-9 expression is high in IDC, but it is of limited prognostic value.
背景/目的：乳腺癌（BC）是沙特女性中最常见的癌症类型。基质金属蛋白酶（MMPs）是能够降解细胞外基质蛋白的内肽酶。在健康个体中，MMPs 的精确调节可防止组织破坏；然而，在癌症中，许多 MMPs 过表达导致组织破坏，使肿瘤细胞能够侵袭和转移。BC 的浸润性导管癌（IDC）分为 1 级（G1）、2 级（G2）和 3 级（G3）肿瘤。
我们使用 Affymetrix Gene 1.0 ST 微阵列对 38 例手术切除的乳腺癌（4 例 G1、17 例 G2 和 17 例 G3）进行了转录组谱分析。使用 Partek Genomic Suite 6.4 鉴定每个等级的差异表达基因，并在蛋白质水平通过免疫组织化学验证表达分析结果。使用适当的软件进行通路分析和发现的临床意义的建立。
我们使用 p<0.05 和倍数变化 >2 的截止值在 BC 等级与正常样本相比鉴定出 1593 个差异表达基因。在这些基因中，有 429 个在所有等级以及肿瘤进展过程中均有表达，而其他许多基因仅与特定等级相关（G1 中有 440 个，G2 中有 203 个，G3 中有 394 个）。微阵列结果表明，与正常乳腺组织相比，MMP-1、-9、-11、-12 和 -13 的 mRNA 表达在较高的 BC 等级中上调。MMP-9 在大多数 IDC（97.5%）样本中表达，在 55%的肿瘤中高表达。MMP-9 的差异表达与组织学 BC 等级显著相关（p=0.03），与总生存期强烈相关（p=0.08）。
基因表达特征是特定等级特有的。较高等级中 MMPs 的过表达可能与 BC 肿瘤的侵袭和转移有关。因此，MMPs，特别是 MMP-9，是可靠的诊断生物标志物和药物靶标候选物，需要进一步进行功能分析以确认其在 BC 中的作用。我们的结果还表明，MMP-9 表达在 IDC 中的发生率较高，但预后价值有限。
