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.
