Researcher:
Korkmaz, Gözde

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Gözde

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Korkmaz

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Korkmaz, Gözde

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    Publication
    Estrogen receptor 1 chromatin profiling in human breast tumors reveals high inter-patient heterogeneity with enrichment of risk SNPs and enhancer activity at most-conserved regions
    (Cold Spring Harbor Lab Press, Publications Dept, 2024) Joosten, Stacey E. P.; Gregoricchio, Sebastian; Stelloo, Suzan; Huang, Chia-Chi Flora; Yavuz, Kerim; Collier, Maria Donaldson; Morova, Tunç; Altıntaş, Umut Berkay; Kim, Yongsoo; Canisius, Sander; Moelans, Cathy B.; van Diest, Paul J.; Vermeulen, Michiel; Linn, Sabine C.; Zwart, Wilbert; Yapıcı, Elif; Korkmaz, Gözde; Lack, Nathan Alan; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); Graduate School of Sciences and Engineering; School of Medicine
    Estrogen Receptor 1 (ESR1;also known as ER alpha, encoded by ESR1 gene) is the main driver and prime drug target in luminal breast cancer. ESR1 chromatin binding is extensively studied in cell lines and a limited number of human tumors, using consensi of peaks shared among samples. However, little is known about inter-tumor heterogeneity of ESR1 chromatin action, along with its biological implications. Here, we use a large set of ESR1 ChIP-seq data from 70 ESR1+ breast cancers to explore inter-patient heterogeneity in ESR1 DNA binding to reveal a striking inter-tumor heterogeneity of ESR1 action. Of note, commonly shared ESR1 sites show the highest estrogen-driven enhancer activity and are most engaged in long-range chromatin interactions. In addition, the most commonly shared ESR1-occupied enhancers are enriched for breast cancer risk SNP loci. We experimentally confirm SNVs to impact chromatin binding potential for ESR1 and its pioneer factor FOXA1. Finally, in the TCGA breast cancer cohort, we can confirm these variations to associate with differences in expression for the target gene. Cumulatively, we reveal a natural hierarchy of ESR1-chromatin interactions in breast cancers within a highly heterogeneous inter-tumor ESR1 landscape, with the most common shared regions being most active and affected by germline functional risk SNPs for breast cancer development.
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    PublicationOpen Access
    Transcriptional factor repertoire of breast cancer in 3D cell culture models
    (Multidisciplinary Digital Publishing Institute (MDPI), 2022) Özkan, Hande; Öztürk, Deniz Gülfem; Korkmaz, Gözde; Researcher; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); School of Medicine; Graduate School of Health Sciences
    Knowledge of the transcriptional regulation of breast cancer tumorigenesis is largely based on studies performed in two-dimensional (2D) monolayer culture models, which lack tissue architecture and therefore fail to represent tumor heterogeneity. However, three-dimensional (3D) cell culture models are better at mimicking in vivo tumor microenvironment, which is critical in regulating cellular behavior. Hence, 3D cell culture models hold great promise for translational breast cancer research. Intratumor heterogeneity of breast cancer is driven by extrinsic factors from the tumor microenvironment (TME) as well as tumor cell-intrinsic parameters including genetic, epigenetic, and transcriptomic traits. The extracellular matrix (ECM), a major structural component of the TME, impacts every stage of tumorigenesis by providing necessary biochemical and biomechanical cues that are major regulators of cell shape/architecture, stiffness, cell proliferation, survival, invasion, and migration. Moreover, ECM and tissue architecture have a profound impact on chromatin structure, thereby altering gene expression. Considering the significant contribution of ECM to cellular behavior, a large body of work underlined that traditional two-dimensional (2D) cultures depriving cell-cell and cell-ECM interactions as well as spatial cellular distribution and organization of solid tumors fail to recapitulate in vivo properties of tumor cells residing in the complex TME. Thus, three-dimensional (3D) culture models are increasingly employed in cancer research, as these culture systems better mimic the physiological microenvironment and shape the cellular responses according to the microenvironmental cues that will regulate critical cell functions such as cell shape/architecture, survival, proliferation, differentiation, and drug response as well as gene expression. Therefore, 3D cell culture models that better resemble the patient transcriptome are critical in defining physiologically relevant transcriptional changes. This review will present the transcriptional factor (TF) repertoire of breast cancer in 3D culture models in the context of mammary tissue architecture, epithelial-to-mesenchymal transition and metastasis, cell death mechanisms, cancer therapy resistance and differential drug response, and stemness and will discuss the impact of culture dimensionality on breast cancer research.