Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Expression data from breast cancer FNA biopsies from patients (US samples)

ABSTRACT: This is Phase II Trial of 4courses of 5-fluorouracil, doxorubicin and cyclophosphamide follwed by 4 additional courses of weekly docetaxel and capecitabine administered as Preoperative Therapy for Patients with Locally Advanced Breast Cancer, Stages II and III by US oncology (PROTOCOL 02-103) We performed gene set analysis (GSA) using functionally annotated gene sets corresponding to almost all known biological processes in ER-positive/HER2negative and ER-negative/HER2-negative breast cancer, respectively. Pre-treatment FNA from primary tumors were obtained and RNA extracted and hybridized to afymetrix microarrays according to manufacturer protocol.

ORGANISM(S): Homo sapiens

SUBMITTER: TAKAYUKI IWAMOTO

PROVIDER: E-GEOD-23988 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Gene pathways associated with prognosis and chemotherapy sensitivity in molecular subtypes of breast cancer.

Iwamoto Takayuki T Bianchini Giampaolo G Booser Daniel D Qi Yuan Y Coutant Charles C Shiang Christine Ya-Hui CY Santarpia Libero L Matsuoka Junji J Hortobagyi Gabriel N GN Symmans William Fraser WF Holmes Frankie A FA O'Shaughnessy Joyce J Hellerstedt Beth B Pippen John J Andre Fabrice F Simon Richard R Pusztai Lajos L

Journal of the National Cancer Institute 20101229 3

<h4>Background</h4>We hypothesized that distinct biological processes might be associated with prognosis and chemotherapy sensitivity in the different types of breast cancers.<h4>Methods</h4>We performed gene set analyses with BRB-ArrayTools statistical software including 2331 functionally annotated gene sets (ie, lists of genes that correspond to a particular biological pathway or biochemical function) assembled from Ingenuity Pathway Analysis and Gene Ontology databases corresponding to almost ...[more]

PMID: 21191116

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Project description:Induced pluripotent stem cell-derived human hepatocyte-like cells (iHeps) could provide a powerful tool for studying the mechanisms underlying human liver development and disease, testing the efficacy and safety of pharmaceuticals across different patients (i.e. personalized medicine), and enabling cell-based therapies in the clinic. However, current in vitro protocols that rely upon growth factors and extracellular matrices (ECM) alone yield iHeps with low levels of liver functions relative to adult primary human hepatocytes (PHHs). Moreover, these low hepatic functions in iHeps are difficult to maintain for prolonged times (weeks to months) in culture. Here, we engineered a micropatterned co-culture (iMPCC) platform in a multi-well format that, in contrast to conventional confluent cultures, significantly enhanced the functional maturation and longevity of iHeps in culture for 4 weeks in vitro when benchmarked against multiple donors of PHHs. In particular, iHeps were micropatterned onto collagen-coated domains of empirically optimized dimensions, surrounded by 3T3-J2 murine embryonic fibroblasts, and then sandwiched with a thin layer of ECM gel (Matrigel™). We assessed iHep maturity via global gene expression profiles, hepatic polarity, secretion of albumin and urea, basal CYP450 activities, phase-II conjugation, drug-mediated CYP450 induction, and drug-induced hepatotoxicity. Conclusion: Controlling both homotypic interactions between iHeps and heterotypic interactions with stromal fibroblasts significantly matures iHep functions and maintains them for several weeks in culture. In the future, iMPCCs could prove useful for drug screening, studying molecular mechanisms underlying iHep differentiation, modeling liver diseases, and integration into human-on-a-chip systems being designed to assess multi-organ responses to compounds. We used Affymetrix microarrays to profile the global gene expression of co-culture stabilized iHeps (iMPCCs) relative to freshly isolated and co-culture stabilized primary human hepatocytes (2 donors). To assess the transcriptomic stability of iHeps in iMPCCs, RNA was extracted following 9 and 21 days of culture for hybridization to Affymetrix microarrays. The hepatic maturation state of iHeps was assessed by comparing gene expression against microarrays containing data from two primary human hepatocyte donors, both following hepatocyte isolation (day 0) and after stabilization in the micropatterened co-culture platform (day 6 and day 42 MPCCs), as previously described.

Project description:The pesticide rotenone, a neurotoxin that inhibits the mitochondrial complex I, and destabilizes microtubules (MT) has been linked to Parkinson disease (PD) etiology and is often used to model this neurodegenerative disease (ND). Many of the mechanisms of action of rotenone are posited mechanisms of neurodegeneration; however, they are not fully understood. Therefore, the study of rotenone-affected functional pathways is pertinent to the understanding of NDs pathogenesis. This report describes the transcriptome analysis of a neuroblastoma (NB) cell line chronically exposed to marginally toxic and moderately toxic doses of rotenone. The results revealed a complex pleiotropic response to rotenone that impacts a variety of cellular events, including cell cycle, DNA damage response, proliferation, differentiation, senescence and cell death, which could lead to survival or neurodegeneration depending on the dose and time of exposure and cell phenotype. The response encompasses an array of physiological pathways, modulated by transcriptional and epigenetic regulatory networks, likely activated by homeostatic alterations. Pathways that incorporate the contribution of MT destabilization to rotenone toxicity are suggested to explain complex I-independent rotenone-induced alterations of metabolism and redox homeostasis. The postulated mechanisms involve the blockage of mitochondrial voltage-dependent anions channels (VDACs) by tubulin, which coupled with other rotenone-induced organelle dysfunctions may underlie many presumed neurodegeneration mechanisms associated with pathophysiological aspects of various NDs including PD, AD and their variant forms. Thus, further investigation of such pathways may help identify novel therapeutic paths for these NDs. SK-N-MC cells were grown in three different conditions: media + vehicle (EtOH), media + a sublethal dose (5 nM) of rotenone, and media + a slightly toxic dose (50 nM) of rotenone. Gene expression was examined at 1 and 4 weeks of rotenone treatment. Three experiments were performed, each lasting 1 and 4 weeks. For each experiment, 5 separate dishes of vehicle-treated, and rotenone-treated cells were harvested at 1 and 4 weeks (30 independent samples at each time point) and pooled into 3 samples (vehicle treated,and rotenone treated with 5 nM and 50 nM) at each time point for a total of 18 individual samples from all thre experiments. Total RNA isolated from each of the 18 individual samples was used to prepared labeled cRNA and hybridized to one Genechip (Affymetrix) Human Genome array HG-U133A at the UCLA microarray core facility (http://microarray.genetics.ucla.edu/). After QC check, the data was normalized and used to assess expression indexes and fold changes (FC > 2.0, compared to vehicle-treated controls) using the model-based expression indexes (MBEI) method implemented in dCHIP, ( http://biosun1.harvard.edu/complab/dchip/), and the Signifiance Analysis of Microarrays (SAM) software for multiple test corrections. Enrichment analysis was performed by the functional annotation tools implemented in DAVID ( http://david.abcc.ncifcrf.gov), to ascertain sets of rotenone DRGs that are enriched in certain biological annotations.

Dataset Information

Expression data from breast cancer FNA biopsies from patients (US samples)

Publications

Gene pathways associated with prognosis and chemotherapy sensitivity in molecular subtypes of breast cancer.

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