ZIA BC 010887 (ZIA) | |||
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Title | Novel Markers for Disease Outcome in Breast Cancer | ||
Institution | NCI, Bethesda, MD | ||
Principal Investigator | Ambs, Stefan | NCI Program Director | N/A |
Cancer Activity | N/A | Division | CCR |
Funded Amount | $399,760 | Project Dates | null - null |
Fiscal Year | 2018 | Project Type | Intramural |
Research Topics w/ Percent Relevance | Cancer Types w/ Percent Relevance | ||
Cancer (100.0%) Chemotherapy (20.0%) Genetic Testing (20.0%) |
Breast (100.0%) | ||
Research Type | |||
Cancer Progression & Metastasis Interactions of Genes and/or Genetic Polymorphisms with Exogenous and/or Endogenous Factors |
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Abstract | |||
Project 1: We continued to comprehensively examine the metabolome, proteome and transcriptome of breast tumors from African-American and European-American patients for biomarker discovery. The promise of this approach is the discovery of markers for prognosis, and of mechanisms that may drive the aggressiveness of breast cancer in African-American women. We previously characterized the metabolomic profile of breast tumors and adjacent non-cancerous tissue from 67 patients and described the differential abundance of more than 200 metabolites. One of them was 2-hydroxyglutarate, which was elevated up to 100-fold in tumors that were primarily estrogen receptor-negative. This accumulation of 2-hydroxyglutarate was closely associated with the co-occurrence of a c-Myc signaling signature in the tumors. In a follow up study, we could show that breast tumors predominately accumulate D-2-hydroxyglutarate and describe the D-2-hydroxyglutarate-producing alcohol dehydrogenase, iron-containing protein 1 (ADHFE1) as a breast cancer oncoprotein that is associated with disease survival. Our data show that ADHFE1 promotes a reductive glutamine metabolism with increased D-2-hydroxyglutarate and mitochondrial reactive oxygen species (ROS) formation. This leads to cellular de-differentiation and enhanced epithelial-mesenchymal transition (EMT), thereby phenocopying alterations in IDH-mutant cancer cells with high D-2-hydroxyglutarate. We also show that D-2-hydroxyglutarate by itself induces EMT and alters metabolism in mammary epithelial cells, including upregulation of both reductive carboxylation of glutamine-derived alpha-ketoglutarate and mitochondrial ROS. We focused our investigations on ADHFE1 because ADHFE1 and MYC locus amplifications co-occur in breast tumors. Additional data indicated the existence of a regulatory feedback loop between c-Myc signaling and ADHFE1 protein expression. The function of ADHFE1 as a candidate oncogene was corroborated when MCF7 human breast cancer cells overexpressing ADHFE1, MYC, or both ADHFE1 and MYC were injected into the mammary gland of mice. ADHFE1 and c-Myc expression not only enhanced tumor growth in a synergistic manner but also increased intratumor levels of 4-hydroxybutyrate (4HB). 4HB is a substrate for ADHFE1 to produce D-2-hydroxyglutarate. Additional research is needed to elucidate the potentially oncogenic function of 4HB synthesis in breast cancer biology. In a different study, focusing on the breast cancer proteome, we performed an integrated proteotranscriptomic characterization of breast tumors. We measured global proteome and transcriptome expression in 118 human breast tumors and adjacent non-cancerous tissues. Comparing proteome with transcriptome data, we found that the proteome describes differences between cancerous and non-cancerous tissue that are not captured by the transcriptome. Moreover, the proteome and transcriptome highlighted partially different tumor biologies. When we applied an integrated analysis of both technologies, the approach revealed a global increase in protein-mRNA concordance in tumors. Highly correlated protein-gene pairs were enriched in protein processing and disease metabolic pathways, and occurred more commonly in tumors of African-American patients. The increased concordance between transcript and protein levels was further associated with aggressive disease, including basal-like/triple-negative tumors, and decreased patient survival. Our study indicates that an integrated analysis of the proteome and transcriptome in cancer can uncover disease characteristics beyond the ability of a single technology. Project 2: Inflammation is widely recognized as an inducer of cancer progression. Inducible nitric oxide synthase (NOS2), cyclooxygenase-2 and cystathionine-beta-synthase (CBS) are candidate inflammation markers and are involved in wound healing, angiogenesis, and carcinogenesis. NOS2 up-regulation and increased nitric oxide (NO) production also affects th |