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Identification of collaboration patterns of dysfunctional pathways in breast cancer.

ABSTRACT: Breast cancer (BC) is the most common malignancy among women. We aimed to illuminate the molecular dysfunctional mechanisms of BC progression. The mRNA expression profile of BC GSE15852 was downloaded from Gene Expression Omnibus database, including 43 normal samples and 43 cancer samples. Differentially expressed genes (DEGs) in BC were screened using the t-test by Benjamin and Hochberg method. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways of the selected DEGs were enriched using Hypergeomeric distribution model. In addition, functional similarity network among the enriched pathways was constructed to further analyze the collaboration of these pathways. We found 848 down-regulated DEGs were associated with 16 significant dysfunctional pathways, including PPAR signaling fatty acid metabolism, and 1584 up-regulated DEGs were related to 6 significant dysfunctional pathways, like cell cycle, protein export, and antigen processing and presentation in BC samples. Crosstalk network analysis of pathways indicated that pyruvate metabolism, propanoate metabolism, and glycolysis gluconeogenesis were the pathways with closest connections with other pathways in BC. In addition, other antigen processing and presentation, including 19 DEGs; PPAR signaling pathway, including 18 DEGs; and pyruvate metabolism pathway, including 13 DEGs were further analyzed. Our results suggested that dysfunctional of significant pathways can greatly affect the progression of BC. Several significant disorder pathways were enriched in our comprehensive study. They may provide guidelines to explore the dysfunctional mechanism of BC progression.

SUBMITTER: Zhu X

PROVIDER: S-EPMC4128997 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Identification of collaboration patterns of dysfunctional pathways in breast cancer.

Zhu Xinyong X Tao Lianyuan L Yao Jing J Sun Pengjun P Pei Lijuan L Li Jiye J Long Zhihua Z Wang Ye Y Zhang Fengliang F

International journal of clinical and experimental pathology 20140615 7

Breast cancer (BC) is the most common malignancy among women. We aimed to illuminate the molecular dysfunctional mechanisms of BC progression. The mRNA expression profile of BC GSE15852 was downloaded from Gene Expression Omnibus database, including 43 normal samples and 43 cancer samples. Differentially expressed genes (DEGs) in BC were screened using the t-test by Benjamin and Hochberg method. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways of the selected DEGs were enriched using Hype ...[more]

PMID: 25120762

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Project description:BACKGROUND:Monitoring treatment and early detection of fatal breast cancer (BC) remains a major unmet need. Aberrant circulating DNA methylation (DNAme) patterns are likely to provide a highly specific cancer signal. We hypothesized that cell-free DNAme markers could indicate disseminated breast cancer, even in the presence of substantial quantities of background DNA. METHODS:We used reduced representation bisulfite sequencing (RRBS) of 31 tissues and established serum assays based on ultra-high coverage bisulfite sequencing in two independent prospective serum sets (n?=?110). The clinical use of one specific region, EFC#93, was validated in 419 patients (in both pre- and post-adjuvant chemotherapy samples) from SUCCESS (Simultaneous Study of Gemcitabine-Docetaxel Combination adjuvant treatment, as well as Extended Bisphosphonate and Surveillance-Trial) and 925 women (pre-diagnosis) from the UKCTOCS (UK Collaborative Trial of Ovarian Cancer Screening) population cohort, with overall survival and occurrence of incident breast cancer (which will or will not lead to death), respectively, as primary endpoints. RESULTS:A total of 18 BC specific DNAme patterns were discovered in tissue, of which the top six were further tested in serum. The best candidate, EFC#93, was validated for clinical use. EFC#93 was an independent poor prognostic marker in pre-chemotherapy samples (hazard ratio [HR] for death?=?7.689) and superior to circulating tumor cells (CTCs) (HR for death?=?5.681). More than 70% of patients with both CTCs and EFC#93 serum DNAme positivity in their pre-chemotherapy samples relapsed within five years. EFC#93-positive disseminated disease in post-chemotherapy samples seems to respond to anti-hormonal treatment. The presence of EFC#93 serum DNAme identified 42.9% and 25% of women who were diagnosed with a fatal BC within 3-6 and 6-12 months of sample donation, respectively, with a specificity of 88%. The sensitivity with respect to detecting fatal BC was?~?4-fold higher compared to non-fatal BC. CONCLUSIONS:Detection of EFC#93 serum DNAme patterns offers a new tool for early diagnosis and management of disseminated breast cancers. Clinical trials are required to assess whether EFC#93-positive women in the absence of radiological detectable breast cancers will benefit from anti-hormonal treatment before the breast lesions become clinically apparent.

Project description:BackgroundLiver cancer is a major global health concern due to the steady increases in its incidence and mortality. Transcription factors, yes-associated protein (YAP) and WW domain-containing transcription regulator protein 1 (WWTR1, also known as TAZ) have emerged as critical regulators in human hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC), the two major types of primary liver cancer. However, our study as well as other previous reports have shown that activation of YAP and TAZ (YAP/TAZ) in adult murine livers is insufficient for the development of liver cancer, suggesting a requirement for an additional oncogenic collaborator for liver carcinogenesis in adulthood. Therefore, we sought to identify the oncogenic partners of YAP/TAZ that promote hepatocarcinogenesis in adults.MethodsData analysis of the transcriptome of patients with liver cancer was performed using the national center for biotechnology information (NCBI) gene expression omnibus (GEO) database and the cancer genome atlas (TCGA). The cancer therapeutics response portal (CTRP) was used to investigate the correlation between sensitivity to chemicals and the copy number of TAZ in human cancer cell lines. Transposons encoding constitutively activated forms of TAZ (TAZS89A), BRAF (BRAFV600E), and PIK3CA (PI3KE545K) were used for hydrodynamic tail vein injection. Mice were monitored at least twice per week and sacrificed when moribund. Tumor-bearing livers were formalin fixed for hematoxylin-eosin staining and immunohistochemistry.ResultsThrough database analyses, we identified EGFR/HER2 signaling to be essential in human cancers with high TAZ activity. Furthermore, immunohistochemical analyses showed that human HCC and CC tissues with high YAP/TAZ activities exhibited concomitant activation of EGFR/HER2 signaling pathways. To demonstrate that EGFR/HER2 signaling promotes YAP/TAZ-mediated hepatocarcinogenesis, TAZS89A was simultaneously expressed in murine adult livers with BRAFV600E or PI3KE545K, activated forms of effector molecules downstream of EGFR/HER2 signaling pathways. Expression of TAZS89A plus BRAFV600E induced HCC, whereas TAZS89A and PI3KE545K led to the development of CC-like cancer.ConclusionsOur study demonstrates that TAZ collaborates with EGFR/HER2 signaling pathways to induce both HCC and CC.

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Identification of collaboration patterns of dysfunctional pathways in breast cancer.

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Identification of collaboration patterns of dysfunctional pathways in breast cancer.

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