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Development of chemoresistance and formation of metastases: New aspects of two major obstacles in breast cancer treatment
Development of chemoresistance and formation of metastases: New aspects of two major obstacles in breast cancer treatment
In this thesis two major hurdles in treatment of breast cancer were investigated, namely the development of chemoresistance as well as the formation of metastases. In the first part it was shown that the development of chemoresistance is a rather individual process without a predetermined pattern (Sommer et al., 2018). The sequential doxorubicin treatment in three independent experiments and the subsequent proteomics analysis revealed pathways being involved in resistance development namely downregulation of apoptotic signaling pathways and upregulation of cell redox homeostasis. Moreover, few proteins with altered expression were identified in all three experiments i.e., downregulation of 60s ribosomal export protein NMD3 (NMD3) and upregulation of 4F2 cell-surface antigen heavy chain (SLC3A2). To further investigate the clinical implication of these two proteins the Kaplan-Meier Plotter was used. Thereby it was shown that both alterations negatively impact the relapse-free survival of luminal A breast cancer patients. Albeit the transferability of in vitro data to clinical settings is limited, the result of this study clearly shows how complex the development of chemoresistance is and might be even more complex in breast cancer patients. These findings further underline that recurrent or persistent tumors might need a different treatment compared to the primary tumor and in case of targeted therapy require an additional biomarker test. As this procedure is not entirely adopted to the clinical praxis a comprehensive diagnosis of residual or recurrent tumor tissue may improve the treatment of breast cancer and thus patient outcome. The second part of this thesis deals with the role of GRK5 in breast cancer metastases. Here, it was shown that GRK5 is mainly expressed in mesenchymal like, triple-negative breast cancer cells and that reduced GRK5 levels clearly hamper the migration and invasion of breast cancer cells (Sommer et al., 2019). Moreover, a comprehensive proteomics approach revealed that pathways being involved in cancer cell migration are mainly affected by down-regulation of GRK5. By stimulating the breast cancer cells with different GPCR ligands, Bombesin was identified as chemoattractant which loses its activity upon GRK5 knock-down. Additional evaluation of the signaling pathway being regulated by GRK5 revealed that GRPR – the cellular receptor of Bombesin – is mainly expressed in TNBC cells. Furthermore, the mRNA level of GRPR and its endogenous ligand GRP decreases by GRK5 knock-down. Finally, it was observed that a knock-down of GRPR hampers the migration of breast cancer cells as well. To evaluate the clinical impact of these findings TNBC cells were treated with sunitinib – an approved multi-kinase inhibitor that is known to inhibit GRK5. Thereby, it was shown that sunitinib treatment reduces cancer cell migration as well as the mRNA levels of GRK5 and GRPR at a non-toxic concentration. Additionally, downstream molecules of GRPR – CDC42 and ROCK1 – were less expressed upon sunitinib treatment and GRK5 knock-down. By utilizing the Kaplan-Meier-Plotter we additionally figured out that the distant metastasis free survival decreases with overexpression of GRK5 and GRPR in breast cancer patients with basal like tumors. With this study a novel signaling pathway that regulates the migration of breast cancer cells was identified. In addition to that the clinical impact of GRK5 and GRPR on the formation of metastases in basal like tumors was shown. Moreover, an approved drug – sunitinib – was found to be able to block this signaling cascade thereby reducing the migratory ability of breast cancer cells. Even though clinical trials would be necessary to prove the efficacy of sunitinib in TNBC this study gives a first hint how the formation of metastases can be overcome and may thus improve patient outcomes. Breast cancer is one of the most prevalent and deadliest diseases in women worldwide. Therefore, it is very important to further investigate mamma carcinoma in clinical but also in pre-clinical settings. This thesis generated further knowledge on the development of chemoresistance and the formation of metastases in vitro. These two obstacles are still major challenges in the treatment of breast cancer patients and worsen their clinical outcome. Thus, each single piece contributing to a better understanding of breast cancer may improve future therapeutic options and treatment regimen.
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Sommer, Ann-Katrin
2021
English
Universitätsbibliothek der Ludwig-Maximilians-Universität München
Sommer, Ann-Katrin (2021): Development of chemoresistance and formation of metastases: New aspects of two major obstacles in breast cancer treatment. Dissertation, LMU München: Faculty of Chemistry and Pharmacy
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Abstract

In this thesis two major hurdles in treatment of breast cancer were investigated, namely the development of chemoresistance as well as the formation of metastases. In the first part it was shown that the development of chemoresistance is a rather individual process without a predetermined pattern (Sommer et al., 2018). The sequential doxorubicin treatment in three independent experiments and the subsequent proteomics analysis revealed pathways being involved in resistance development namely downregulation of apoptotic signaling pathways and upregulation of cell redox homeostasis. Moreover, few proteins with altered expression were identified in all three experiments i.e., downregulation of 60s ribosomal export protein NMD3 (NMD3) and upregulation of 4F2 cell-surface antigen heavy chain (SLC3A2). To further investigate the clinical implication of these two proteins the Kaplan-Meier Plotter was used. Thereby it was shown that both alterations negatively impact the relapse-free survival of luminal A breast cancer patients. Albeit the transferability of in vitro data to clinical settings is limited, the result of this study clearly shows how complex the development of chemoresistance is and might be even more complex in breast cancer patients. These findings further underline that recurrent or persistent tumors might need a different treatment compared to the primary tumor and in case of targeted therapy require an additional biomarker test. As this procedure is not entirely adopted to the clinical praxis a comprehensive diagnosis of residual or recurrent tumor tissue may improve the treatment of breast cancer and thus patient outcome. The second part of this thesis deals with the role of GRK5 in breast cancer metastases. Here, it was shown that GRK5 is mainly expressed in mesenchymal like, triple-negative breast cancer cells and that reduced GRK5 levels clearly hamper the migration and invasion of breast cancer cells (Sommer et al., 2019). Moreover, a comprehensive proteomics approach revealed that pathways being involved in cancer cell migration are mainly affected by down-regulation of GRK5. By stimulating the breast cancer cells with different GPCR ligands, Bombesin was identified as chemoattractant which loses its activity upon GRK5 knock-down. Additional evaluation of the signaling pathway being regulated by GRK5 revealed that GRPR – the cellular receptor of Bombesin – is mainly expressed in TNBC cells. Furthermore, the mRNA level of GRPR and its endogenous ligand GRP decreases by GRK5 knock-down. Finally, it was observed that a knock-down of GRPR hampers the migration of breast cancer cells as well. To evaluate the clinical impact of these findings TNBC cells were treated with sunitinib – an approved multi-kinase inhibitor that is known to inhibit GRK5. Thereby, it was shown that sunitinib treatment reduces cancer cell migration as well as the mRNA levels of GRK5 and GRPR at a non-toxic concentration. Additionally, downstream molecules of GRPR – CDC42 and ROCK1 – were less expressed upon sunitinib treatment and GRK5 knock-down. By utilizing the Kaplan-Meier-Plotter we additionally figured out that the distant metastasis free survival decreases with overexpression of GRK5 and GRPR in breast cancer patients with basal like tumors. With this study a novel signaling pathway that regulates the migration of breast cancer cells was identified. In addition to that the clinical impact of GRK5 and GRPR on the formation of metastases in basal like tumors was shown. Moreover, an approved drug – sunitinib – was found to be able to block this signaling cascade thereby reducing the migratory ability of breast cancer cells. Even though clinical trials would be necessary to prove the efficacy of sunitinib in TNBC this study gives a first hint how the formation of metastases can be overcome and may thus improve patient outcomes. Breast cancer is one of the most prevalent and deadliest diseases in women worldwide. Therefore, it is very important to further investigate mamma carcinoma in clinical but also in pre-clinical settings. This thesis generated further knowledge on the development of chemoresistance and the formation of metastases in vitro. These two obstacles are still major challenges in the treatment of breast cancer patients and worsen their clinical outcome. Thus, each single piece contributing to a better understanding of breast cancer may improve future therapeutic options and treatment regimen.