03079cam a2200349 a 4500 EG-GiCUC 20250223032610.0 201010s2020 ua dh f m 000 0 eng d EG-GiCUC eng EG-GiCUC eng Deposite Ph.D Cai01.19.02.Ph.D.2020.Ya.T Yasmin Mostafa Attia Targeting signaling pathways activated in drug resistant breast cancer cell line / Yasmin Mostafa Attia ; Supervised Samia A. Shouman , Salama A. Salama , Gabriel B. Lopez استهداف المسارات النشطة المفعلة فى خلايا سرطان الثدى المقاومة للادوية Cairo : Yasmin Mostafa Attia , 2020 148 P. : charts , facsimile ; 25cm Thesis (Ph.D.) - Cairo University - National Cancer Institute - Department of Cancer Biology Background:Tamoxifen is the gold-standard endocrine therapy for estrogen receptor positive (ER+) breast cancer. Nonetheless, tamoxifen resistance is a challenging clinical problem. Transcriptional activation of ER-Ü can be stimulated by cyclin-dependent kinase 7 (CDK7), which plays an important role in the regulation of cell cycle and the expression of genes involved in tumor progression and resistance to tamoxifen. Aim of the work: To study the potential modulatory role of CDK7 inhibitor in tamoxifen response and to explore its mechanistic pathways in the tamoxifen sensitive, MCF-7 and tamoxifen-resistant LCC2, breast cancer cell lines; in two orthotopic xenograft models, as well as in clinical samples. Methods: The cytotoxic effect of CDK7 inhibition, alone and in combination with tamoxifen was studied in vitro, in both tamoxifen-sensitive and resistant cell lines, as well as in orthotopic breast cancer mouse models. Drug interaction was evaluated using the isobologram equation. Apoptosis was evaluated by flow cytometry and TUNEL assay. The expression of angiogenesis marker (CD31), cell cycle regulatory proteins as well as downstream oncogenic markers were determined by flow cytometry and western blotting. Moreover, analysis of TCGA breast cancer data and the microarray data of patients receiving tamoxifen were investigated to evaluate the role of CDK7 in tamoxifen resistance. Results: The current in vitro study showed that CDK7 inhibitors either by siRNA or pharmacologically by THZ1 decreased the expression of activated estrogen receptor-Ü (p-ER-Ü S118) and downregulated the of essential oncogenes such as MYC, STAT3 and Ý{u2013}catenin expression which plays a crucial role in tamoxifen resistance Issued also as CD Breast cancer Cyclin dependent kinase (CDK7) Estrogen Receptor (ER) Gabriel B. Lopez , Supervisor Salama A. Salama , Supervisor Samia A. Shouman , Supervisor http://172.23.153.220/th.pdf Nazla Revisor Shimaa Cataloger ddc TH 78138 78138 ddc 0 CUCL cl210 2024-02-11 Cai01.19.02.Ph.D.2020.Ya.T 01010110081710000 2023-09-22 00:00:00 TH ddc 0 CUCL cl2u8 2024-02-11 Cai01.19.02.Ph.D.2020.Ya.T 01020110081710000 2023-09-22 00:00:00 81710.CD CD