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2 results on '"Karagoz, Kubra"'

1. Aggressive Mammary Cancers Lacking Lymphocytic Infiltration Arise in Irradiated Mice and Can Be Prevented by Dietary Intervention

Author

Omene, Coral, Ma, Lin, Moore, Jade, Ouyang, Haoxu, Illa-Bochaca, Irineu, Chou, William, Patel, Manan S, Sebastiano, Christopher, Demaria, Sandra, Mao, Jian-Hua, Karagoz, Kubra, Gatza, Michael L, and Barcellos-Hoff, Mary Helen

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Immunology, Stem Cell Research - Nonembryonic - Non-Human, Prevention, Cancer, Stem Cell Research, Breast Cancer, Age Factors, Animals, CD8-Positive T-Lymphocytes, Diet, Dose-Response Relationship, Radiation, Female, Inflammation, Lymphocytes, Tumor-Infiltrating, Mammary Neoplasms, Experimental, Mice, Mice, Inbred BALB C, Mice, Knockout, Neoplasms, Radiation-Induced, Transcriptome, Tumor Microenvironment, Tumor Suppressor Protein p53, Pharmacology and Pharmaceutical Sciences, Oncology and carcinogenesis
Abstract

Because the incidence of breast cancer increases decades after ionizing radiation exposure, aging has been implicated in the evolution of the tumor microenvironment and tumor progression. Here, we investigated radiation-induced carcinogenesis using a model in which the mammary glands of 10-month-old BALB/c mice were transplanted with Trp53-null mammary tissue 3 days after exposure to low doses of sparsely ionizing γ-radiation or densely ionizing particle radiation. Mammary transplants in aged, irradiated hosts gave rise to significantly more tumors that grew more rapidly than those in sham-irradiated mice, with the most pronounced effects seen in mice irradiated with densely ionizing particle radiation. Tumor transcriptomes identified a characteristic immune signature of these aggressive cancers. Consistent with this, fast-growing tumors exhibited an immunosuppressive tumor microenvironment with few infiltrating lymphocytes, abundant immunosuppressive myeloid cells, and high COX-2 and TGFβ. Only irradiated hosts gave rise to tumors lacking cytotoxic CD8+ lymphocytes (defined here as immune desert), which also occurred in younger irradiated hosts. These data suggest that host irradiation may promote immunosuppression. To test this, young chimera mice were fed chow containing a honeybee-derived compound with anti-inflammatory and immunomodulatory properties, caffeic acid phenethyl ester (CAPE). CAPE prevented the detrimental effects of host irradiation on tumor growth rate, immune signature, and immunosuppression. These data indicated that low-dose radiation, particularly densely ionizing exposure of aged mice, promoted more aggressive cancers by suppressing antitumor immunity. Dietary intervention with a nontoxic immunomodulatory agent could prevent systemic effects of radiation that fuel carcinogenesis, supporting the potential of this strategy for cancer prevention.

Published
2020

2. Multi-Omic Data Interpretation to Repurpose Subtype Specific Drug Candidates for Breast Cancer

Author

Beste Turanli, Kubra Karagoz, Gholamreza Bidkhori, Raghu Sinha, Michael L. Gatza, Mathias Uhlen, Adil Mardinoglu, Kazim Yalcin Arga, Turanli, Beste, Karagoz, Kubra, Bidkhori, Gholamreza, Sinha, Raghu, Gatza, Michael L., Uhlen, Mathias, Mardinoglu, Adil, and Arga, Kazim Yalcin

Subjects
0301 basic medicine, Oncology, medicine.medical_specialty, lcsh:QH426-470, repurposing, Context (language use), Disease, drug repositioning, basal subtype, Interactome, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, breast cancer, TARGETS, Internal medicine, non-cancer therapeutics, REVEALS, medicine, Genetics, Genetics (clinical), Original Research, business.industry, MOLECULAR PORTRAITS, personalized metabolic models, PROLIFERATION, Cancer, ENTROPY, medicine.disease, 3. Good health, Drug repositioning, lcsh:Genetics, 030104 developmental biology, Drug development, 030220 oncology & carcinogenesis, Cardiovascular agent, Molecular Medicine, business, GENOMICS
Abstract

Triple-negative breast cancer (TNBC), which is largely synonymous with the basal-like molecular subtype, is the 5th leading cause of cancer deaths for women in the United States. The overall prognosis for TNBC patients remains poor given that few treatment options exist; including targeted therapies (not FDA approved), and multi-agent chemotherapy as standard-of-care treatment. TNBC like other complex diseases is governed by the perturbations of the complex interaction networks thereby elucidating the underlying molecular mechanisms of this disease in the context of network principles, which have the potential to identify targets for drug development. Here, we present an integrated "omics" approach based on the use of transcriptome and interactome data to identify dynamic/active protein-protein interaction networks (PPINs) in TNBC patients. We have identified three highly connected modules, EED, DHX9, and AURKA, which are extremely activated in TNBC tumors compared to both normal tissues and other breast cancer subtypes. Based on the functional analyses, we propose that these modules are potential drivers of proliferation and, as such, should be considered candidate molecular targets for drug development or drug repositioning in TNBC. Consistent with this argument, we repurposed steroids, anti-inflammatory agents, anti-infective agents, cardiovascular agents for patients with basal-like breast cancer. Finally, we have performed essential metabolite analysis on personalized genome-scale metabolic models and found that metabolites such as sphingosine-1-phosphate and cholesterol-sulfate have utmost importance in TNBC tumor growth.

Published
2019

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