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Results for “expression profiling”

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PubMed2005

Comparison of (-)-epigallocatechin-3-gallate elicited liver and small intestine gene expression profiles between C57BL/6J mice and C57BL/6J/Nrf2 (-/-) mice.

PURPOSE: This study was conducted to study global gene expression profiles elicited by (-)-epigallocatechin-3-gallate (EGCG) in mouse liver and small intestine, as well as to identify EGCG-regulated Nrf2-dependent genes. METHODS: C57BL/6J and C57BL/6J/Nrf2(-/-) mice were given an oral dose of EGCG at 200 mg/kg or treated with vehicle. Both liver and small intestine were collected 3 h and 12 h after treatment. Total RNA was extracted from the tissues and gene expression profiles were analyzed using Affymetrix mouse genome 430 2.0 array and GeneSpring 6.1 software. Microarray data were validated using quantitative real-time reverse transcription-PCR chain reaction analysis. RESULTS: Genes that were either induced or suppressed more than two fold by EGCG treatment compared with vehicle treatment in the same genotype group were filtered using the GeneSpring software. Among these well-defined genes, 671 EGCG-regulated Nrf2-dependent genes and 256 EGCG-regulated Nrf2-independent genes were identified in liver, whereas 228 EGCG-regulated Nrf2-dependent genes and 98 EGCG-regulated Nrf2-independent genes were identified in the small intestine. Based on their biological functions, these genes mainly fall into the category of ubiquitination and proteolysis, electron transport, detoxification, transport, cell growth and apoptosis, cell adhesion, kinase and phosphatases, and transcription factors. CONCLUSIONS: Genes expressed in mouse liver are more responsive to oral treatment of EGCG than those expressed in small intestine. EGCG could regulate many genes in both organs in an Nrf2-dependent manner. The identification of genes related to detoxification, transport, cell growth and apoptosis, cell adhesion, kinase, and transcription regulated by EGCG not only provide potential novel insight into the effect of EGCG on global gene expression and chemopreventive effects, but also point to the potential role of Nrf2 in these processes.

Animals↗

PubMed2004

Identification and handling of artifactual gene expression profiles emerging in microarray hybridization experiments.

Mathematical methods of analysis of microarray hybridizations deal with gene expression profiles as elementary units. However, some of these profiles do not reflect a biologically relevant transcriptional response, but rather stem from technical artifacts. Here, we describe two technically independent but rationally interconnected methods for identification of such artifactual profiles. Our diagnostics are based on detection of deviations from uniformity, which is assumed as the main underlying principle of microarray design. Method 1 is based on detection of non-uniformity of microarray distribution of printed genes that are clustered based on the similarity of their expression profiles. Method 2 is based on evaluation of the presence of gene-specific microarray spots within the slides' areas characterized by an abnormal concentration of low/high differential expression values, which we define as 'patterns of differentials'. Applying two novel algorithms, for nested clustering (method 1) and for pattern detection (method 2), we can make a dual estimation of the profile's quality for almost every printed gene. Genes with artifactual profiles detected by method 1 may then be removed from further analysis. Suspicious differential expression values detected by method 2 may be either removed or weighted according to the probabilities of patterns that cover them, thus diminishing their input in any further data analysis.

Algorithms↗

PubMed2002

Analysis of 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced gene expression profile in vivo using pathway-specific cDNA arrays.

In the current study, we used pathway-specific cDNA arrays to detect the transcriptional signature induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in vivo by studying simultaneously the expression profiles of 83 genes involved in apoptosis, cytokine production and angiogenesis. To this end, C57BL/6 mice were injected i.p. with 50 microg/kg body weight of TCDD and 1 or 3 days later, the thymus was analyzed for gene expression profiles. In the thymus, 23 out of 37 apoptotic genes screened were up-regulated by TCDD by a factor of two or more when compared to the vehicle-treated controls. In contrast, in the spleen, 20 out of 22 and in the liver, 16 out of 37 apoptotic genes were up-regulated. In the thymus, several genes encoding caspases, and members of the TNF family, including Fas ligand, were induced. Also, in the thymus, eight out of 23, and in the spleen, six out of 23 cytokine genes were up-regulated. In the liver and to a lesser extent in the thymus, certain angiogenesis genes were induced while others were repressed. When mice were injected with 0.1, 1, 10 or 50 microg/kg body weight of TCDD and the thymus was analyzed for apoptotic genes 1 day later, a dose-dependent response was not seen with most apoptotic genes. However, certain apoptotic genes were induced in the thymus even at low doses of 0.1 microg/kg body weight of TCDD. These data demonstrate that TCDD alters the expression of a large array of genes involved in apoptosis, cytokine production and angiogenesis. Thus, pathway-specific cDNA arrays may help in the identification of specific gene expression profiles induced by xenobiotics and to delineate the molecular mechanisms of toxicity.

Animals↗

PubMed2004

Expression profiles of androgen independent bone metastatic prostate cancer cells indicate up-regulation of the putative serine-threonine kinase GS3955.

PURPOSE: We established gene expression profiles by gene array analysis in the LNCaP model of human prostate cancer progression and evaluated genes differentially expressed in the androgen independent and bone metastatic C4-2 cell line compared to the androgen dependent and nonmetastatic parental LNCaP cell line. MATERIALS AND METHODS: Gene expression profiles were generated using Atlas cDNA arrays (Clontech, Palo Alto, California), comprising 1,176 genes. Intrinsic expression of the novel serine/threonine kinase GS3955 in LNCaP, C4-2 and PC-3 prostate cancer cells, and expression when stimulated with growth factors, was monitored by real-time reverse transcriptase-polymerase chain reaction. Furthermore, expression in human tumor specimens was evaluated. Cellular localization of GS3955 protein was analyzed by expressing it as a fusion with green fluorescent protein. RESULTS: Comparable numbers of genes were up-regulated and down-regulated in C4-2 compared to LNCaP. The novel serine/threonine kinase GS3955 was markedly up-regulated (greater than 40-fold) in C4-2, differentially regulated in LNCaP and C4-2 by insulin-like growth factor-1, and variably expressed in human prostate tumor specimens. Moreover, GS3955 was shown to localize in the cell cytoplasm and nucleus. CONCLUSIONS: Differential expression and mitogenic regulation of the serine/threonine kinase GS3955 in LNCaP and C4-2 suggest its functional involvement in the development of androgen independence and/or metastatic potential. GS3955 is also expressed in human prostate cancer specimens and further analysis may provide insights into the biology of prostate cancer progression.

Androgens↗

PubMed2006

Hormone-replacement therapy influences gene expression profiles and is associated with breast-cancer prognosis: a cohort study.

BACKGROUND: Postmenopausal hormone-replacement therapy (HRT) increases breast-cancer risk. The influence of HRT on the biology of the primary tumor, however, is not well understood. METHODS: We obtained breast-cancer gene expression profiles using Affymetrix human genome U133A arrays. We examined the relationship between HRT-regulated gene profiles, tumor characteristics, and recurrence-free survival in 72 postmenopausal women. RESULTS: HRT use in patients with estrogen receptor (ER) protein positive tumors (n = 72) was associated with an altered regulation of 276 genes. Expression profiles based on these genes clustered ER-positive tumors into two molecular subclasses, one of which was associated with HRT use and had significantly better recurrence free survival despite lower ER levels. A comparison with external data suggested that gene regulation in tumors associated with HRT was negatively correlated with gene regulation induced by short-term estrogen exposure, but positively correlated with the effect of tamoxifen. CONCLUSION: Our findings suggest that post-menopausal HRT use is associated with a distinct gene expression profile related to better recurrence-free survival and lower ER protein levels. Tentatively, HRT-associated gene expression in tumors resembles the effect of tamoxifen exposure on MCF-7 cells.

Breast Neoplasms↗

PubMed2002

Gene expression profile after intense second messenger activation in cortical primary neurones.

Numerous stimuli induce immediate early gene (IEG) expression in neurones, but a comprehensive overview of the late-response genes is lacking. Therefore we aimed to identify changes in the neuronal gene expression profile following intense stimulation. Forskolin and 12-O-tetradecanoylphorbol-13-acetate (TPA), direct activators of intracellular second messengers, were applied to primary cultured cortical neurones. The gene expression profiles were analyzed on Affymetrix DNA chips which cover around 8000 rat genes. Out of these, 95 genes (1.2%) were increased at least three-fold, and 43 genes (0.5%) were at least three-fold decreased. The gene chip results were verified by testing 15 of the altered genes by quantitative real-time PCR. The majority of the up-regulated genes were transcription factors, neurotrophic factors or (putative) neuropeptides. Furthermore, there were marked changes in intracellular signal processing enzymes and in postsynaptic structural proteins (e.g. vesl, arc, narp), which have been implicated in synaptic plasticity. Notably, classical players in neurotransmission or plasticity such as glutamate and GABA receptors or voltage-gated ion channels were not increased. It is likely that the increased production of components of intracellular signalling and of postsynaptic proteins is involved in neuronal plasticity.

Animals↗

PubMed2006

RNA expression profiling at the single molecule level.

We developed a microarray platform for PCR amplification-independent expression profiling of minute samples. A novel scanning system combined with specialized biochips enables detection down to individual fluorescent oligonucleotide molecules specifically hybridized to their complementary sequence over the entire biochip surface of cm2 size. A detection limit of 1.3 fM target oligonucleotide concentration--corresponding to only 39,000 molecules in the sample solution--and a dynamic range of 4.7 orders of magnitude have been achieved. The applicability of the system to PCR amplification-independent gene-expression profiling of minute samples was demonstrated by complex hybridization of cDNA derived from the equivalent of only 10(4) cells, which matches results obtained in ensemble studies on large samples. By counting each hybridized molecule on the microarray, the method is insusceptible to gene-specific variations of the labeling, thereby representing a principle advance to conventional ensemble-based microarray analysis.

Cell Line↗

PubMed2003

Gene expression profiling of multiple histone deacetylase (HDAC) inhibitors: defining a common gene set produced by HDAC inhibition in T24 and MDA carcinoma cell lines.

Acetylation of histones in chromatin is one mechanism involved in the regulation of gene transcription and is tightly controlled by the balance of acetyltransferase and deacetylase (HDAC) activities. In cancer, some genes are repressed by the inappropriate recruitment of HDACs, e.g., tumor suppressor genes. To understand the genomic effects of HDAC inhibition on gene transcription we studied the gene expression profiles of T24 bladder and MDA breast carcinoma cells treated with three HDAC inhibitors, suberoylanilide hydroxamic acid, trichostatin A, and MS-27-275. The gene expression profiles of the HDAC inhibitors were generally similar to one another and differed substantially from those produced by structurally related inactive analogues; consequently, the changes in gene expression are mechanism-based. Hierarchical clustering of expression profiles demonstrated a greater similarity between the two hydroxamate-containing inhibitors (suberoylanilide hydroxamic acid and trichostatin A) than with MS-27-275. This difference was also supported by cell phenotypic experiments. As many genes were down-regulated as up-regulated by HDAC inhibitor treatment. Comparison of the data sets defined a common ("core") set of 13 genes regulated by all of the HDAC inhibitors in three cell lines, 8 up-regulated and 5 down-regulated. Ten of 13 genes were confirmed in dose response studies in T24 cells by quantitative-PCR. The core regulated genes are involved predominantly in cell cycle/apoptosis and DNA synthesis in response to HDAC inhibitors. These data will aide in understanding the complex set of events in cells in response to chromatin remodeling induced by HDAC inhibition, which may be responsible for antitumor effects.

Benzamides↗

PubMed2006

Gene expression profiling in biliary epithelial cells of primary biliary cirrhosis using laser capture microdissection and cDNA microarray.

UNLABELLED: Primary biliary cirrhosis (PBC) is a chronic, cholestatic liver disease characterized by progressive destruction of interlobular bile ducts that leads to biliary cirrhosis. To elucidate the etiology of PBC, the gene expression profile in biliary epithelial cells (BECs) was analyzed. Liver specimens of 5 PBC, 3 chronic hepatitis C (CHC), and 3 normal subjects were obtained. BECs were selectively collected by laser capture microdissection (LCM), RNA were obtained by extraction and amplification with T7 RNA polymerase, and a cDNA microarray analysis was performed. The following genes exhibited increased expression in BEC of PBC, as compared with CHC or normal subjects: human leukocyte antigen DQ alpha 1 (HLA-DQA-1), carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), and vascular cell adhesion molecule 1 (VCAM-1). The immunohistochemistry for HLA-DQA-1, CEACAM1, TRAIL, and VCAM-1 confirmed these results. Furthermore, two-way cluster analysis showed that the gene expression profiling in BEC of PBC were categorized into a separate cluster, distinct from CHC or normal subjects. CONCLUSIONS: The gene expression profiling in BEC of PBC differed from those of CHC and normal subjects, and the genes concerning local immune response, such as HLA-DQA-1, CEACAM1, TRAIL, and VCAM-1, exhibited increased expression, indicating that they were involved in the development of bile duct injury.

Adult↗

PubMed2005

Expression profiles of mouse dendritic cell sarcoma are similar to those of hematopoietic stem cells or progenitors by clustering and principal component analyses.

We isolated and screened two tumor cell clones DD1 and DG6 with different capacity of metastasis from the same parent cell line, a mouse dendritic cell (DC) sarcoma, using limited dilution method. The genome-wide expressions of DD1 and DG6 cells were detected by Affymetrix's MOE-430A microarray. The expression profiles related with mouse DC development were downloaded from GEO at NCBI and ArrayExpress at EBI database. In order to compare the expression of DC sarcoma and DC developmental arrays which was performed by MG-U74av2, we had screened the best matched probesets between MOE-430A and MG-U74av2 according to the probe identities from Affymetrix technical annotation. After the normalization of 11 housekeeping genes across the 34 arrays (2 DC sarcoma and 32 DC developmental arrays), all these expression profiles were analyzed by the methods of hierarchical clustering, principal component analysis, nearest-neighborhood, and self-organizing maps. The results indicate that expression profiles of DC sarcoma are closer to those of the DC progenitors and hematopoietic stem cells from bone marrow compared with the sorted DCs from spleen. The results support the hypothesis that cancers (tumors or sarcomas) arise from stem cells. It is suggested that the DC sarcomas are more similar to the DC progenitors and hematopoietic stem cells than the relative mature DCs in gene expressions on the large-scale.

Animals↗

PubMed2005

High-resolution mapping of genomic imbalance and identification of gene expression profiles associated with differential chemotherapy response in serous epithelial ovarian cancer.

Array comparative genomic hybridization (aCGH) and microarray expression profiling were used to subclassify DNA and RNA alterations associated with differential response to chemotherapy in ovarian cancer. Two to 4 Mb interval arrays were used to map genomic imbalances in 26 sporadic serous ovarian tumors. Cytobands 1p36, 1q42-44, 6p22.1-p21.2, 7q32.1-q34 9q33.3-q34.3, 11p15.2, 13q12.2-q13.1, 13q21.31, 17q11.2, 17q24.2-q25.3, 18q12.2, and 21q21.2-q21.3 were found to be statistically associated with chemotherapy response, and novel regions of loss at 15q11.2-q15.1 and 17q21.32-q21.33 were identified. Gene expression profiles were obtained from a subset of these tumors and identified a group of genes whose differential expression was significantly associated with drug resistance. Within this group, five genes (GAPD, HMGB2, HSC70, GRP58, and HMGB1), previously shown to form a nuclear complex associated with resistance to DNA conformation-altering chemotherapeutic drugs in in vitro systems, may represent a novel class of genes associated with in vivo drug response in ovarian cancer patients. Although RNA expression change indicated only weak DNA copy number dependence, these data illustrate the value of molecular profiling at both the RNA and DNA levels to identify small genomic regions and gene subsets that could be associated with differential chemotherapy response in ovarian cancer.

Cell Nucleus↗

PubMed2003

Gene expression profile of adult T-cell acute lymphocytic leukemia identifies distinct subsets of patients with different response to therapy and survival.

Gene expression profiles were examined in 33 adult patients with T-cell acute lymphocytic leukemia (T-ALL). Nonspecific filtering criteria identified 313 genes differentially expressed in the leukemic cells. Hierarchical clustering of samples identified 2 groups that reflected the degree of T-cell differentiation but was not associated with clinical outcome. Comparison between refractory patients and those who responded to induction chemotherapy identified a single gene, interleukin 8 (IL-8), that was highly expressed in refractory T-ALL cells and a set of 30 genes that was highly expressed in leukemic cells from patients who achieved complete remission. We next identified 19 genes that were differentially expressed in T-ALL cells from patients who either had a relapse or remained in continuous complete remission. A model based on the expression of 3 of these genes was predictive of duration of remission. The 3-gene model was validated on a further set of T-ALL samples from 18 additional patients treated on the same clinical protocol. This study demonstrates that gene expression profiling can identify a limited number of genes that are predictive of response to induction therapy and remission duration in adult patients with T-ALL.

Adult↗

PubMed2006

Gene expression profiling of early follicular development in primordial, primary, and secondary follicles.

OBJECTIVE: To study global gene expression profiles of early folliculogenesis in primordial, primary, and secondary follicles. DESIGN: A cDNA microarray study using amplified RNAs from isolated follicles. SETTING: Experimental animal study. ANIMAL(S): Female ICR strain mice (12 days old). INTERVENTION(S): Isolation of follicles at each stage, RNA isolation and amplification, microarray hybridization, and statistical analysis for microarray. MAIN OUTCOME MEASURE(S): Gene lists of various functional groups with an estimated false discovery rate of 5%. Among them, platelet-derived growth factors (PDGFs) and receptors were localized by immunohistochemistry in mouse ovaries. RESULT(S): We analyzed a list of genes according to function, such as apoptosis, cell cycle, cell proliferation and maintenance, cytoskeleton, extracellular matrix, and signal transduction, as well as according to frequency. Among the list of genes, we found all PDGFs (A, B, C, and D) and receptors (alpha and beta) are expressed with differential expression patterns in the oocytes and ovarian cells according to stage of follicular development. CONCLUSION(S): The present report suggests that genome-wide expression profiling using microarray after RNA amplification may become a useful tool to better understand the molecular mechanism(s) involved in early ovarian folliculogenesis.

Animals↗

PubMed2006

Expression profiling of mucinous tumors of the ovary identifies genes of clinicopathologic importance.

PURPOSE: To elucidate the molecular mechanisms contributing to the unique clinicopathologic characteristics of mucinous ovarian carcinoma, global gene expression profiling of mucinous ovarian tumors was carried out. EXPERIMENTAL DESIGN: Gene expression profiling was completed for 25 microdissected mucinous tumors [6 cystadenomas, 10 low malignant potential (LMP) tumors, and 9 adenocarcinomas] using Affymetrix U133 Plus 2.0 oligonucleotide microarrays. Hierarchical clustering and binary tree prediction analysis were used to determine the relationships among mucinous specimens and a series of previously profiled microdissected serous tumors and normal ovarian surface epithelium. PathwayAssist software was used to identify putative signaling pathways involved in the development of mucinous LMP tumors and adenocarcinomas. RESULTS: Comparison of the gene profiles between mucinous tumors and normal ovarian epithelial cells identified 1,599, 2,916, and 1,765 differentially expressed in genes in the cystadenomas, LMP tumors, and adenocarcinomas, respectively. Hierarchical clustering showed that mucinous and serous LMP tumors are distinct. In addition, there was a close association of mucinous LMP tumors and adenocarcinomas with serous adenocarcinomas. Binary tree prediction revealed increased heterogeneity among mucinous tumors compared with their serous counterparts. Furthermore, the cystadenomas coexpressed a subset of genes that were differentially regulated in LMP and adenocarcinoma specimens compared with normal ovarian surface epithelium. PathwayAssist highlighted pathways with expression of genes involved in drug resistance in both LMP and adenocarcinoma samples. In addition, genes involved in cytoskeletal regulation were specifically up-regulated in the mucinous adenocarcinomas. CONCLUSIONS: These data provide a useful basis for understanding the molecular events leading to the development and progression of mucinous ovarian cancer.

Adenocarcinoma, Mucinous↗

PubMed2004

Comprehensive analysis of differential gene expression profiles on carbon tetrachloride-induced rat liver injury and regeneration.

Microarray analysis of RNA from carbon tetrachloride (CCl4)-administered rat livers was performed at various time points to establish a global gene expression profile during injury and regeneration stages. A single dose of 1 ml/kg of CCl4 was given by ip injection, and the liver samples were obtained after 6, 24, 48 h, and 2 weeks. Histopathologic, biochemical, and immunohistochemical studies enabled the classification of the CCl4 effect into injury (6 and 24 h) and regeneration (48 h and 2 weeks) stages. The expression levels of 5180 clones on a custom rat gene microarray were analyzed and 587 clones yielded changeable gene expression on at least single time point. One hundred seventy-nine clones were classified as injury-specific clones, while 38 clones as regeneration-specific clones. Characteristic gene expression profiles could be associated with CCl4-induced gene expression with the disruption of lipid metabolism, which is known to cause the fatty liver induced by CCl4 treatment. In addition, induction of the transcripts for many ribosomal proteins was detected during the injury stage, particularly at the 24-h time point, despite the previous report of decreased protein synthesis rate upon CCl4 treatment. Several genes with known functions were also identified as CCl4-regulated genes. In conclusion, we established a global gene expression profile utilizing microarray analysis in rat liver upon acute CCl4 administration with a full chronological profile that not only covers injury stage but also later points of regeneration stage.

Animals↗

PubMed1996

Expression profiling of mRNA obtained from single identified crustacean motor neurons: determination of specificity of hybridization.

The purpose of this study was to determine if the technique of expression profiling would allow us to determine the changes in the abundance of certain mRNAs in identifiable, single neurons as a result of heightened electrical activity. In doing so we developed an approach to test the specificity of hybridization in expression profiling. Messenger RNA from single identified crayfish motor neurons was amplified by ligation-mediated reverse transcription PCR and hybridized by dot-blotting to 45 target cDNAs from different species. As a test of specificity, the hybridization was repeated using unlabelled cDNAs, the dots were excised, and the hybridized nucleic acids were re-amplified, cloned, and sequenced to confirm their identity. By cloning and sequencing the re-amplified product for each cDNA examined, one can determine the degree of background hybridization as compared to homologous hybridization. False positive results were also observed when a species-specific cDNA and highly stringent hybridization conditions were used. Our results demonstrate that ligation-mediated PCR is a useful technique for checking the specificity of expression profiling. This approach can easily be adapted to any situation when confirmation of the specificity of nucleic acid hybridization is required. During this study, part of a novel crayfish neuronal actin cDNA was cloned and sequenced.

Animals↗

PubMed2003

Gene-expression profiling of CD34+ cells from various hematopoietic stem-cell sources reveals functional differences in stem-cell activity.

The replacement of bone marrow (BM) as a conventional source of stem cell (SC) by umbilical cord blood (UCB) and granulocyte-colony stimulating factor-mobilized peripheral blood SC (PBSC) has brought about clinical advantages. However, several studies have demonstrated that UCB CD34(+) cells and PBSC significantly differ from BM CD34(+) cells qualitatively and quantitatively. Here, we quantified the number of SC in purified BM, UCB CD34(+) cells, and CD34(+) PBSC using in vitro and in vivo assays for human hematopoietic SC (HSC) activity. A cobblestone area-forming cell (CAFC) assay showed that UCB CD34(+) cells contained the highest frequency of CAFC(wk6) (3.6- to tenfold higher than BM CD34(+) cells and PBSC, respectively), and the engraftment capacity in vivo by nonobese diabetic/severe combined immunodeficiency repopulation assay was also significantly greater than BM CD34(+), with a higher proportion of CD45(+) cells detected in the recipients at a lower cell dose. To understand the molecular characteristics underlying these functional differences, we performed several DNA microarray experiments using Affymetrix gene chips, containing 12,600 genes. Comparative analysis of gene-expression profiles showed differential expression of 51 genes between BM and UCB CD34(+) SC and 64 genes between BM CD34(+) cells and PBSC. These genes are involved in proliferation, differentiation, apoptosis, and engraftment capacity of SC. Thus, the molecular expression profiles reported here confirmed functional differences observed among the SC sources. Moreover, this report provides new insights to describe the molecular phenotype of CD34(+) HSC and leads to a better understanding of the discrepancy among the SC sources.

Animals↗

PubMed2006

Gene expression profiling of ATP-binding cassette (ABC) transporters as a predictor of the pathologic response to neoadjuvant chemotherapy in breast cancer patients.

Drug resistance is a major obstacle to the successful chemotherapy. Several ATP-binding cassette (ABC) transporters including ABCB1, ABCC1 and ABCG2 have been known to be important mediators of chemoresistance. Using oligonucleotide microarrays (HG-U133 Plus 2.0; Affymetrix), we analyzed the ABC transporter gene expression profiles in breast cancer patients who underwent sequential weekly paclitaxel/FEC (5-fluorouracil, epirubicin and cyclophosphamide) neoadjuvant chemotherapy. We compared the ABC transporter expression profile between two classes of pretreatment tumor samples divided by the patients' pathological response to neoadjuvant chemotherapy (residual disease [RD] versus pathologic complete response [pCR]) ABCB3, ABCC7 and ABCF2 showed significantly high expression in the pCR. Several ABC transporters including ABCC5, ABCA12, ABCA1 ABCC13, ABCB6 and ABCC11 showed significantly increased expression in the RD (p<0.05). We evaluated the feasibility of developing a multigene predictor model of pathologic response to neoadjuvant chemotherapy using gene expression profiles of ABC transporters. The prediction error was evaluated by leave-one-out cross-validation (LOOCV). A multigene predictor model with the ABC transporters differentially expressed between the two classes (p<or=0.003) showed an average 92.8% of predictive accuracy (95% CI, 88.0-97.4%) with a 93.2% (95% CI, 85.2-100%) positive predictive value for pCR, a 93.6% (95% CI, 87.8-99.4%) negative predictive value, a sensitivity of 88.1%(95% CI, 76.8-99.4%), and a specificity of 95.9% (91.1% CI, 87.8-100%). Our results suggest that several ABC transporters in human breast cancer cells may affect the clinical response to neoadjuvant chemotherapy, and transcriptional profiling of these genes may be useful to predict the pathologic response to sequential weekly paclitaxel/FEC in breast cancer patients.

ATP-Binding Cassette Transporters↗