Meme kanserinde CRISPR/Cas9 yöntemi ile WWOX ve WBP2 genlerinin düzenlenmesinin tamoksifen direnci üzerine etkisinin araştırılması
Date
2024-06-25
Authors
Bulut, Ebrucan
Journal Title
Journal ISSN
Volume Title
Publisher
Bursa Uludağ Üniversitesi
Abstract
Meme kanseri, farklı alt tipleri bulunan heterojen bir hastalıktır ve kadınlar arasında en sık görülen kanser türüdür. Tedaviye karşı gelişen direnç, etkin tedavi oluşturulmasında ciddi bir engeldir. Meme kanserlerinin yaklaşık %70'ini oluşturan östrojen reseptör pozitif (ER+) meme kanserli hastalarda, Tamoksifen tedavisi yaygın olarak kullanılır. Ancak, Tamoksifen'in yan etkileri ve gelişen ilaç direnci tedavideki önemli sorunlardır. Östrojen sinyalizasyonundaki düzensizliklerin tedavi başarısızlığına katkıda bulunduğu bilinmektedir. Son yıllarda yapılan çalışmalarda Hippo sinyal yolağındaki değişimlerin ilaç direnci gelişiminde rol oynadığı gösterilmiştir. Hippo yolağı, hücrenin kök hücre özelliklerini, apoptozu ve proliferasyonunu düzenler. WWOX geni, çeşitli kanserlerin ilerlemesinde rol oynayan bir tümör baskılayıcı gendir ve yüksek ekspresyonu etkin Tamoksifen tedavisi ile ilişkilidir. WWOX'un down regülasyonunun Hippo yolağıyla ilişkili Tamoksifen direncine neden olduğu düşünülse de WWOX'un ligandı WBP2’nin Tamoksifen direnciyle ilişkisi tam olarak bilinmemektedir. Bu nedenle mevcut çalışmada, WWOX ve WBP2 genlerinin Hippo sinyal yolağı ile ilişkisi incelendi. CRISPR/Cas9 gen düzenleme yöntemi kullanılarak MCF-7 ve tamoksifen dirençli MCF-7 hücre dizinlerinde bu genlerin Tamoksifen direncindeki potansiyel etkinliği araştırıldı. Ayrıca, WWOX ve WBP2'nin ER+ meme kanseri hastalarında Tamoksifen direnci için terapötik hedef ve prognostik biyobelirteç olma potansiyelleri değerlendirildi. Elde edilen bulguların, ER+ meme kanserinde Hippo yolağı ile ilişkili Tamoksifen direnç gelişim mekanizmasının anlaşılmasına ve etkin tedavi yöntemlerinin geliştirilmesine katkı sağlayacağı öngörüldü.
Breast cancer, characterized by its heterogeneity and various subtypes, is the most prevalent cancer among women. The emergence of resistance to therapy poses a significant obstacle to achieving effective treatment outcomes. In approximately 70% of breast cancer cases, which are estrogen receptor-positive (ER+), Tamoxifen therapy is a common treatment modality. However, the adverse effects and development of resistance to Tamoxifen present substantial challenges. Dysregulation in estrogen signaling pathways is known to contribute to therapeutic failure. The Hippo signaling pathway has been implicated in the development of drug resistance, regulating critical cellular processes such as stem cell properties, apoptosis, and proliferation. The WWOX gene, a known tumor suppressor, plays a crucial role in the progression of various cancers, and its high expression has been correlated with effective Tamoxifen therapy. Although the downregulation of WWOX is believed to contribute to Tamoxifen resistance through the Hippo pathway, the involvement of WWOX ligand WBP2 in this resistance mechanism remains unclear. This study aims to elucidate the relationship between WWOX and WBP2 genes and the Hippo signaling pathway. Using the CRISPR/Cas9 gene editing technique, the potential role of these genes in Tamoxifen resistance was investigated in both MCF-7 and Tamoxifen-resistant MCF-7 cell lines. Furthermore, the study assessed the therapeutic target and prognostic biomarker potential of WWOX and WBP2 in ER+ breast cancer patients concerning Tamoxifen resistance. The findings are anticipated to contribute to a deeper understanding of the mechanisms underlying Hippo pathway-related Tamoxifen resistance in ER+ breast cancer and to the development of more effective treatment strategies.
Breast cancer, characterized by its heterogeneity and various subtypes, is the most prevalent cancer among women. The emergence of resistance to therapy poses a significant obstacle to achieving effective treatment outcomes. In approximately 70% of breast cancer cases, which are estrogen receptor-positive (ER+), Tamoxifen therapy is a common treatment modality. However, the adverse effects and development of resistance to Tamoxifen present substantial challenges. Dysregulation in estrogen signaling pathways is known to contribute to therapeutic failure. The Hippo signaling pathway has been implicated in the development of drug resistance, regulating critical cellular processes such as stem cell properties, apoptosis, and proliferation. The WWOX gene, a known tumor suppressor, plays a crucial role in the progression of various cancers, and its high expression has been correlated with effective Tamoxifen therapy. Although the downregulation of WWOX is believed to contribute to Tamoxifen resistance through the Hippo pathway, the involvement of WWOX ligand WBP2 in this resistance mechanism remains unclear. This study aims to elucidate the relationship between WWOX and WBP2 genes and the Hippo signaling pathway. Using the CRISPR/Cas9 gene editing technique, the potential role of these genes in Tamoxifen resistance was investigated in both MCF-7 and Tamoxifen-resistant MCF-7 cell lines. Furthermore, the study assessed the therapeutic target and prognostic biomarker potential of WWOX and WBP2 in ER+ breast cancer patients concerning Tamoxifen resistance. The findings are anticipated to contribute to a deeper understanding of the mechanisms underlying Hippo pathway-related Tamoxifen resistance in ER+ breast cancer and to the development of more effective treatment strategies.
Description
2022-ACIL-08-21348-TÜSEB
2022-A2-YL-27690-TÜSEB
Keywords
Hippo yolağı, EMT, Tamoksifen, Hippo pathway, Tamoxifen, WWOX, WBP2