The Molecular Profile of Inflammatory Breast Cancer

炎性乳腺癌的分子概况

• 批准号: 7291844
• 负责人: STEFAN AMBS
• 金额: --
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7291844
• 关键词: Molecular; Profile; Inflammatory; Breast; Cancer

Develop gene expression profiles of microdissected tumors that distinguish: 1) inflammatory breast cancer (IBC) from other breast cancers (non-IBC), and 2) stromal tissue of IBC tumors from stromal tissue of non-IBC tumors. Breast cancer is a heterogeneous disease that can be subclassified into several tumor types. IBC is the most aggressive form of breast cancer. IBC is a locally advanced breast cancer that affects women at an earlier age than other types of breast carcinoma. The disease is characterized by a high tumor microvessel density and dermal lymphatic invasion that causes the inflammatory symptoms, fast disease progression, and by extremely poor survival. Although the frequency of IBC among breast cancer cases in the US is only about 3-5 percent, it appears to be much more common in other geographic areas, such as North Africa. The causes of IBC are unknown and both environmental and genetic risk factors are thought to be involved. The early onset of the disease, the strong angiogenicity and propensity of IBC to invade vessels, and the large disparity in the IBC incidence among various populations are indicators of genetic predisposition and inherited susceptibility. Both low- and high-risk cancer susceptibility genes may determine the risk for IBC. Two genes, WISP3 and RhoC GTPase, have recently been identified that are differently expressed in IBC when compared with non-IBC. WISP3 is a putative tumor suppressor gene for the disease, and may regulate the insulin-like growth factor pathway. RhoC GTPase is an overexpressed oncogene in IBC, and modulates the induction of angiogenic factors in breast cells.We hypothesize that IBC has a distinct expression profile in tumor and normal surrounding tissue (stroma) that predicts the risk of metastasis and poor survival. Our objective is to identify genes that are preferentially expressed in tumors and surrounding normal tissue of patients with IBC by comparing the IBC gene expression profile with the profile of non-IBC breast tumors. This is a novel approach. IBC is a rare disease, and it is difficult to collect flash-frozen IBC specimens that are suitable for array-based gene expression analysis. We have a particular interest in those genes that promote metastasis, and are expressed in the stroma, but not in cancer cells. To date, no report describes an expression profile in stroma that is associated with tumor metastasis and poor survival. However, a molecular signature of metastasis in primary breast tumors contained genes that are thought to be expressed in normal tissue, but not by cancer cells.We identified 22 IBC and 46 non-IBC tumors, and 10 normal breast tissue samples for a genome-wide gene expression study. Of those, we microdissected 14 specimens from IBC patients, 19 specimens from non-IBC patients with poor survival (#5 years), 15 specimens from non-IBC patients with good survival (greater than 5 years), and 10 breast reduction cases from noncancer patients. We are using laser-captured microdissection to collect both tumor and stromal tissue from each specimen. mRNA expression is analyzed on the Affymetrix HG-U133A GeneChip. We are currently analyzing the expression data with the help of a biostatistician. Preliminary results indicate that the expression profiles of the tumor stroma are significantly different between IBC and non-IBC tumors. It appears that there is a greater difference between IBC and non-IBC tumors based on the gene expression of the tumor stroma than the gene expression of the tumor epithelium.

开发出分歧的微解析肿瘤的基因表达谱：1）炎性乳腺癌（IBC）与其他乳腺癌（非IBC）和2）IBC肿瘤的基质组织与非IBC肿瘤的基质组织。乳腺癌是一种异质性疾病，可以分为几种肿瘤类型。 IBC是乳腺癌最具侵略性的形式。 IBC是一种局部晚期乳腺癌，比其他类型的乳腺癌更早地影响女性。该疾病的特征是高肿瘤微血管密度和皮肤淋巴侵袭，导致炎症症状，快速疾病进展以及生存率极差。尽管美国乳腺癌病例中IBC的频率仅为3-5％，但在其他地理区域（例如北非）似乎更为常见。 IBC的原因是未知的，环境和遗传危险因素都被认为涉及。疾病的早​​期发作，IBC入侵血管的强血管生成性和倾向，以及各种人群中IBC发病率的巨大差异是遗传倾向和遗传易感性的指标。低风险和高危癌敏感性基因都可能决定IBC的风险。与非IBC相比，最近已经鉴定出了在IBC中在IBC中表达的两个基因，即WISP3和RHOC GTPase。 WISP3是该疾病的推定肿瘤抑制基因，可能调节胰岛素样生长因子途径。 RHOC GTPase是IBC中一种过表达的癌基因，并调节了乳腺细胞中血管生成因子的诱导。我们假设IBC在肿瘤和正常周围组织（基质）中具有明显的表达特征，可以预测转移和不良存活的风险。我们的目标是通过将IBC基因表达谱与非IBC乳腺肿瘤的谱进行比较，鉴定在肿瘤和周围的IBC患者正常组织中优先表达的基因。这是一种新颖的方法。 IBC是一种罕见的疾病，很难收集适合基于阵列的基因表达分析的闪光闪烁的IBC标本。我们对那些促进转移的基因特别感兴趣，并在基质中表达，但在癌细胞中不表达。迄今为止，尚未描述与肿瘤转移和存活不良有关的基质中的表达谱。然而，原发性乳腺肿瘤中转移的分子特征包含被认为在正常组织中表达的基因，但不能通过癌细胞表达。我们鉴定了22个IBC和46个非IBC肿瘤，以及10个基因组基因表达研究的正常乳腺组织样品。在其中，我们从IBC患者中进行了微调，来自IBC患者的14个标本，非生存率较差（＃5年）的19例标本，来自非IBC患者的15例标本（大于5年）和10例非癌症患者的乳房减少病例。我们使用激光捕获的显微减退来从每个标本中收集肿瘤和基质组织。在Affymetrix HG-U133A Genechip上分析mRNA表达。我们目前正在借助生物统计学家分析表达数据。初步结果表明，IBC和非IBC肿瘤之间肿瘤基质的表达谱图显着差异。看来，基于肿瘤基质的基因表达，IBC和非IBC肿瘤之间的差异要大于肿瘤上皮的基因表达。