Inflammatory versus non-inflammatory breast cancers. Inflammatory versus non-inflammatory breast cancers

Inflammatory Breast Cancer (IBC) is the most aggressive form of breast carcinoma characterized by the rapid onset of inflammatory signs. The molecular fingerprint for this rare, severe and unique clinical entity is still not elucidated. The goal of the present work was to detect both gene expression levels and alternate RNA splice variants specific to IBC. Experimental Design: In order to identify differentially expressed genes and splicing events, we performed splice-sensitive array profiling using Affymetrix Exon Array and quantitative RT-PCR analyses in a large series of 177 IBC compared to 183 non-IBC. We also assessed the prognostic value of the identified candidate genes and splice variants. Results: A 5-splice signature (HSPA8, RPL10, RPL4, DIDO1 and EVL) was able to distinguish IBC from non-IBC tumors (p<10-7). This splice signature was associated with poor metastasis-free survival (MFS) in hormone receptor-negative non-IBC (p=0.02), whereas it had no prognostic value in IBC patients. A PAM analysis of deregulated genes in IBC compared to non-IBC identified a 10-gene signature highly predictive of IBC phenotype and conferring a poor prognosis in non-IBC. The most up-regulated genes in IBC were 3 hemoglobin genes able to highly discriminate IBC from non IBC (p<10-4). In epithelial breast tumor cells, Hb protein expression was confirmed by immunohistochemistry. Conclusions: IBC has a specific spliced transcript profile that deserves further functional studies. Above all, IBC is characterized by hemoglobin genes overexpression, a fact that may lead to increased tumor progression. If confirmed, hemoglobins may serve as therapeutic targets. Overall design: Training set of 33 IBC and 28 non IBC

炎性乳腺癌（Inflammatory Breast Cancer, IBC）是最具侵袭性的乳腺癌亚型，以快速出现炎症体征为典型特征。这种罕见、危重且具有独特临床表型的病症，其分子特征迄今尚未阐明。本研究旨在检测IBC特异性的基因表达水平与可变RNA剪接变体。
实验设计：为鉴定差异表达基因与剪接事件，本研究采用Affymetrix外显子芯片（Affymetrix Exon Array）开展剪接敏感型芯片分析，并结合定量逆转录聚合酶链反应（quantitative RT-PCR），对177例IBC样本与183例非IBC样本进行大队列分析。此外，本研究还评估了所鉴定的候选基因及剪接变体的预后价值。
结果：一个包含5种剪接特征的基因集（HSPA8、RPL10、RPL4、DIDO1及EVL）可有效区分IBC与非IBC肿瘤（p<10^-7）。该剪接特征在激素受体阴性的非IBC患者中与较差的无转移生存期（metastasis-free survival, MFS）显著相关（p=0.02），但在IBC患者中无预后价值。对IBC与非IBC间差异表达基因开展的微阵列预测分析（Prediction Analysis of Microarrays, PAM），鉴定出一个包含10个基因的特征集，该特征集可高度预测IBC表型，并在非IBC患者中提示不良预后。IBC中上调最显著的基因为3个血红蛋白基因，其可高效区分IBC与非IBC（p<10^-4）。免疫组化实验证实了乳腺上皮肿瘤细胞中血红蛋白（Hemoglobin, Hb）蛋白的表达。
结论：炎性乳腺癌具有独特的剪接转录本谱，值得开展进一步的功能研究。尤为关键的是，炎性乳腺癌以血红蛋白基因过表达为特征，这一现象可能促进肿瘤进展。若该结论得以验证，血红蛋白可作为潜在治疗靶点。
整体实验设计：包含33例IBC与28例非IBC样本的训练集。