<> "The repository administrator has not yet configured an RDF license."^^ . <> . . "TNFα-activated fibroblasts support tumor progression in Luminal A breast cancer"^^ . "Breast carcinoma is the leading cause of cancer-related death in women worldwide. The most common breast cancer subtype is Luminal A. Most patients with this subtype initially respond well to standard endocrine therapies. However, many of them develop metastasis years later. It is well-known that the tumor microenvironment (TME) plays an important role in supporting tumor progression. A major component of the TME are the cancer-associated fibroblasts (CAFs), which have been reported to have multiple tumor-promoting functions. The exact mechanisms though are still under investigation, and no successful anti-CAF therapies have been discovered yet. \r\nIn my PhD studies, presented in this thesis, I investigated the role of CAFs in Luminal A breast cancer progression. To this end, I utilized CAFs isolated from Luminal A patient biopsies, as well as the classical in vitro models of Luminal A breast cancer – the MCF7 and T47D cell lines. In the TME, CAFs are exposed to many factors that activate them and drive them into a tumor-promoting phenotype. Previously, it has been shown that the combination of TNFα and TGFβ1 was sufficient to confer CAF-like properties on CAF precursor cells. Therefore, to mimic CAF activation in vitro, I stimulated the CAFs with these two cytokines. To study how the cytokine-activated CAFs could support breast cancer progression, the effect of CAF-conditioned medium (CM) on migration, autophagy and recovery post chemotherapy was examined in MCF7 and T47D cells. The goal was to identify novel CAF-secreted factors and/or signaling pathways that they activate in the breast cancer cells to support Luminal A relapse. To this aim, via mass spectrometry analysis, I studied the effect of the stimulation on the CAF secretome and full proteome. In addition, utilizing RNA sequencing, I investigated the effect of the cytokine-activated CAF CM on the MCF7 cells, and compared it to the effect of the CM from unstimulated CAFs. Finally, I compared the results from both analyses to better understand the complex crosstalk between CAFs and Luminal A breast cancer cells and how it could contribute to Luminal A breast cancer progression. \r\nFirst, I demonstrated that the stimulation with TNFα was sufficient to induce the CAFs to secrete factors with pro-migratory effect on the Luminal A cells. Second, I was able to identify upregulation of STAT/IFNβ1 signaling in the CAFs in response to the TNFα stimulation. In addition, the CAFs were able to relay the STAT signaling to the breast cancer cells via secretion of IFNβ1. Third, I identified STAT2 to work in a STAT1-independent manner as the transcription factor necessary for the TNFα-stimulated induction of the ISG (interferon-stimulated gene) signature in the CAFs. Although I could not show a clear connection between the CAF interferon signaling and the breast cancer migratory phenotype, the stimulation with TNFα appeared to potentially impede with the CAFs ability to support Luminal A recovery post chemotherapy. Thus, TNFα seemed to play a double role in the complex CAF-Luminal A crosstalk. While TNFα-stimulated CAFs secreted factors, which increased Luminal A breast cancer migration, some of these factors and/or even TNFα itself seemed to prevent the recovery of the tumor cells after chemotherapy. Further investigation of the complex CAF-Lum A crosstalk and the role of TNFα in it is necessary. Meanwhile the role of TNFα as a double-edge sword in the TME-cancer crosstalk is something to consider when deciding on the next best therapeutic option for treatment of refractory Luminal A breast cancer."^^ . "2022" . . . . . . . "Zhivka Ivanova"^^ . "Hristova"^^ . "Zhivka Ivanova Hristova"^^ . . . . . . "TNFα-activated fibroblasts support tumor progression in Luminal A breast cancer (PDF)"^^ . . . "PhD THESIS ZHIVKA HRISTOVA.pdf"^^ . . . "TNFα-activated fibroblasts support tumor progression in Luminal A breast cancer (Other)"^^ . . . . . . "lightbox.jpg"^^ . . . "TNFα-activated fibroblasts support tumor progression in Luminal A breast cancer (Other)"^^ . . . . . . "preview.jpg"^^ . . . "TNFα-activated fibroblasts support tumor progression in Luminal A breast cancer (Other)"^^ . . . . . . "medium.jpg"^^ . . . "TNFα-activated fibroblasts support tumor progression in Luminal A breast cancer (Other)"^^ . . . . . . "small.jpg"^^ . . . "TNFα-activated fibroblasts support tumor progression in Luminal A breast cancer (Other)"^^ . . . . . . "indexcodes.txt"^^ . . "HTML Summary of #32207 \n\nTNFα-activated fibroblasts support tumor progression in Luminal A breast cancer\n\n" . "text/html" . . . "500 Naturwissenschaften und Mathematik"@de . "500 Natural sciences and mathematics"@en . . . "570 Biowissenschaften, Biologie"@de . "570 Life sciences"@en . . . "610 Medizin"@de . "610 Medical sciences Medicine"@en . .