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- W3118742562 abstract "The breast cancer subtype Luminal B is diagnosed in 20% of all breast cancer cases whereas only 50 % of the patients are still alive 5 years after the first diagnosis. Despite the advances in treatment, patients suffering from Luminal B breast cancer frequently experience a relapse or develop distant metastases. Besides the current strategy of hormone-receptor-positivity, proliferation indices, grading, and gene signature assays to categorize the Luminal breast cancer patients into high and low-risk groups, there is still a lack of appropriate markers that reliably predict events of recurrence. Overall, this thesis aims to identify biomarkers that are associated with aggressivity, cell dissemination and/or metastases formation. Importantly these markers might contribute to the therapy decision if Luminal B breast cancer patients need a chemotherapeutic intervention or not. Therefore, the primary Luminal B patient samples were analyzed and PDX models were generated by the transplantation of primary Luminal B patient samples into NSG mice, the so-called tumor mouse (TM). Additionally, humanized Luminal B tumor mice (HTM) were generated and assessed under the influence of the human immune system. The phenotypic analysis of the primary patient samples revealed that a high expression of CD24 in Luminal B breast cancer patients differs from Luminal A breast cancer patients. The occurrence of MICs (CD44+/cMET+/CD47+) in the high-risk Luminal B tumors (patients that died, suffered from a relapse, or when the PDX model was successful) compared with low-risk Luminal B tumors (patients that are alive, without a relapse, and where the PDX model failed) could serve as a marker for the identification of high-risk Luminal B breast cancer patients. Remarkably, tumor cells of lung metastases differed phenotypically to those of the primary tumor, showing an increased CD44 and cMET expression in the TM, as well as in the patient metastases (e.g. pleural effusion and ascites). Enhanced expression of cMET and CD44 in Luminal B metastases were determined to be independent of the absence or the presence of a human immune system. Moreover, an increased CD4/CD8 ratio was determined as an indicator of a high-risk Luminal B tumor. However, the most important finding was the dependence of MDM2 amplification to form highly aggressive tumors accompanied by the high probability for metastatic spread in Luminal B TM and HTM. When MDM2 was amplified in tumors, the metastases preferentially were found in the lung of the PDX model, and DTCs in the bone marrow. This means that an amplification of MDM2 in Luminal breast cancer characterizes the patients as high-risk patients. These findings were confirmed in vitro by a MDM2 knockdown experiment, showing a p53 mediated mechanism of apoptosis and cell proliferation. Targeting MDM2 by AMG232 inhibition revealed increased apoptosis and reduced proliferation, which demonstrated the potential clinical relevance. TP53 mutation was also detected as a high-risk marker in Luminal B TM as this alteration in the primary tumor promoted BM DTCs. MDM4 amplification was verified to promote metastatic spread into various organs, such as the lung, the liver, the brain, and the BM, and subclassifies the tumor as a high-risk tumor. All the determined genomic alterations of MDM2, p53, and MDM4 regulate each other, which shows the importance of the pathway for high-risk Luminal B breast cancer. Single cell sequencing revealed one cluster formation of primary tumor with specific genomic losses and gains and another cluster mainly formed by DTCs. The differences in copy number profiles were preferentially shown by DTCs that derived from HTM PDX but not from TM, implicating a selection pressure in the periphery potentially evoked by human immune cells. Moreover, a selection determined by the bone marrow niche, which is altered by human immune cells in the HTM, could enable DTCs with a special genetic profile to colonize. The low immunogenicity of Luminal B tumors was demonstrated in primary patient samples and in the HTM, rendering the Luminal B HTM PDX as an adequate model to analyze Luminal B breast cancer. These models could be useful for preclinical immune-modulatory studies in Luminal B breast cancer in the future.In summary, we showed the suitability of Luminal B PDX and humanized PDX models that are able to identify geno- and phenotypic markers that predict a high potential for metastatic spread and aggressiveness of the tumor. However, prospectively further studies on MDM2 amplification and MDM2 expression in Luminal B breast cancer have to be validated in large patient cohorts. Further clinical studies should determine if breast cancer patients with genetic MDM2/MDM4/TP53 predisposition might additionally benefit from cytotoxic intervention or from specific MDM2 targeting (e.g., by MDM2 inhibitors)." @default.
- W3118742562 created "2021-01-18" @default.
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- W3118742562 date "2021-01-01" @default.
- W3118742562 modified "2023-09-27" @default.
- W3118742562 title "Evaluation of geno- and phenotypic alterations in Luminal B breast cancer using tumor mice (TM) and humanized tumor mice (HTM)" @default.
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