Project description:Brain metastasis is one of the most feared complications of cancer and the most common intracranial malignancy in adults. Its underlying mechanisms remain unknown. From breast cancer patients with metastatic disease we isolated cell populations that aggressively colonize the brain. Transcriptomic analysis of these cells yielded overlapping gene sets whose expression is selectively associated with brain metastasis. The expression of seventeen of these genes in primary breast tumors is associated with brain relapse in breast cancer patients. Some of these genes are also associated with metastasis to lung but not to liver, bone or lymph nodes, providing a molecular basis for the long-observed link between brain and lung metastasis. Among the functionally validated brain metastasis genes, the cyclooxigenase COX-2, the EGFR ligand HB-EGF, and the brain-specific 2-6 sialyltransferase ST6GALNAC5 mediate cancer cell passage through the blood-brain barrier. Other brain metastasis genes encode inflammatory factors and brain-specific proteolytic regulators, suggesting a multifaceted program for breast cancer colonization of the brain. Experiment Overall Design: 204 primary tumors from breast cancer patients with known site of relapse were studied, focussing on brain relapse versus other relapse. Identified genes were validated in this cohort.
Project description:Analysis of breast cancer tumors following fulvestrant treatment for 4 weeks. Fulvestrant is a highly specific ER antagonist used to treat postmenopausal women with breast cancer. Data provide insight into the molecular mechanism of action of fulvestrant on whole genome expression.
Project description:Purpose: A number of microarray studies have reported distinct molecular profiles of breast cancers (BC): basal-like, ErbB2-like and two to three luminal-like subtypes. These were associated with different clinical outcomes. However, although the basal and the ErbB2 subtypes are repeatedly recognized, identification of estrogen receptor (ER)-positive subtypes has been inconsistent. Refinement of their molecular definition is therefore needed. Materials and methods: We have previously reported a gene-expression grade index (GGI) which defines histological grade based on gene expression profiles. Using this algorithm, we assigned ER-positive BC to either high or low genomic grade subgroups and compared these to previously reported ER-positive molecular classifications. As further validation, we classified 666 ER-positive samples into subtypes and assessed their clinical outcome. Results: Two ER-positive molecular subgroups (high and low genomic grade) could be defined using the GGI. Despite tracking a single biological pathway, these were highly comparable to the previously described luminal A and B classification and significantly correlated to the risk groups produced using the 21-gene recurrence score. The two subtypes were associated with statistically distinct clinical outcome in both systemically untreated and tamoxifen-treated populations. Conclusions: The use of genomic grade can identify two clinically distinct ER-positive molecular subtypes in a simple and highly reproducible manner across multiple datasets. This study emphasizes the important role of proliferation-related genes in predicting prognosis in ER-positive BC. Experiment Overall Design: dataset of microarray experiments from primary breast tumors used to assess the reationship between GGI, molecular subtypes, and tamoxifen resistance. Experiment Overall Design: No replicate, no reference sample.
Project description:More than two thirds of breast cancers express the estrogen receptor (ER) and depend on estrogen for growth and survival. Therapies targeting ER function including aromatase inhibitors that block the production of estrogens and ER antagonists that alter ER transcriptional activity play a central role in the treatment of ER+ breast cancers of all stages. In contrast to ER- breast cancers, which frequently harbor mutations in the p53 tumor suppressor, ER+ breast cancers are predominantly wild type for p53. Despite harboring wild type p53, ER+ breast cancer cells are resistant to chemotherapy-induced apoptosis in the presence of estrogen. Using genome-wide approaches we have addressed the mechanism by which ER antagonizes the pro-apoptotic function of p53. Interestingly both ER agonists such as estradiol and selective ER modulators (SERM) such as tamoxifen promote p53 antagonism. In contrast the full ER antagonist fulvestrant blocks the ability of ER to inhibit p53-mediated cell death. This suggests an improved strategy for the treatment of ER+ breast cancer utilizing antagonists that completely block ER action together with drugs that activate p53-mediated cell death. MCF7 cells were hormone-depleted for 3 days and then treated with 10 uM doxorubicin for 12 hours
Project description:Gene expression profiles of human breast cancer tissues from 100 different patients treated with primary systemic chemotherapy (Gemcitabine, Epirubicin and Docetaxel) Keywords: expression profiling Human breast cancer tissues from 100 patients have been used to perform expression profiling analysis.
Project description:"Gene transcription in a set of 49 human primary lung adenocarcinomas and 9 normal lung tissue samples was examined using Affymetrix GeneChip technology. We aimed to investigate differential gene expression between the two tissue types. A total of 3,442 genes, called the set MAD, were found to be either up- or down-regulated by at least two fold between the two phenotypes. Genes assigned to a particular gene ontology term were found, in many cases, to be significantly unevenly distributed between the genes in and outside MAD. Terms that were overrepresented in MAD included functions directly implicated in cancer cell metabolism. Based on their functional roles and expression profiles, genes in MAD were grouped into likely co-regulated gene sets."
Project description:Coculture of primary pancreatic cancer cells and cancer associated fibroblasts (CAF) in vitro to study the cross talk between these cells
Project description:Comparisons among breast cancer metastases at different organs revealed distinct microenvironments as characterized by cytokine content. Such microenvironment distinction might be important to dictate how the cancer cells adapt to survival before they successfully colonize. Experiment Overall Design: 58 breast cancer metastases from different organs were profiled and compared by the expression level of over 400 cytokines. 29 samples were incuded in this series. 29 others as well as 7 in the present series were profiled on U133A platforms and included in series GSE14018.
Project description:Carcinomas of unknown primary (CUP) are characterized by early metastatic dissemination in the absence of a detectable primary tumor. This disease accounts for about 3% of all malignant tumors. Most CUPs are poorly responsive to chemotherapy and have a rapid fatal evolution. The biological mechanisms supporting metastatic growth in various sites combined with regression or absence of growth in the primary site are still poorly understood. The aim of this project was to investigate characteristics of gene expression profile specific of CUPs with special attention to genes overexpressed or silenced in CUPs but not in classical secondary metastases. Three series of experiments were performed in 2006 and 2007. In all experiments, the mRNA used as a reference was obtained from diploid untransformed human fibroblasts (MRC5). The CUP samples were 2 xenografted CUP tumors (Capi1 and Capi3) and 4 CUP biopsies including a squamous carcinoma (Aud) and 3 adenocarcinomas (Gal, Pro, Gag). Samples representative of secondary metastases were xenografted tumors derived from metastases of nasopharyngeal carcinoma (C17), lung adenocarcinoma (IC14) and pancreatic adenocarcinoma (xenografted Capan 1 cell line) and one biopsy from a breast carcinoma (Vuc).