TY - JOUR A1 - Löb, Sanja A1 - Linsmeier, Eva A1 - Herbert, Saskia-Laureen A1 - Schlaiß, Tanja A1 - Kiesel, Matthias A1 - Wischhusen, Jörg A1 - Salmen, Jessica A1 - Kranke, Peter A1 - Quenzer, Anne A1 - Kurz, Florian A1 - Weiss, Claire A1 - Gerhard-Hartmann, Elena A1 - Wöckel, Achim A1 - Diessner, Joachim T1 - Prognostic effect of HER2 evolution from primary breast cancer to breast cancer metastases JF - Journal of Cancer Research and Clinical Oncology N2 - Purpose Therapeutic options for breast cancer (BC) treatment are constantly evolving. The Human Epidermal Growth Factor 2 (HER2)-low BC entity is a new subgroup, representing about 55% of all BC patients. New antibody–drug conjugates demonstrated promising results for this BC subgroup. Currently, there is limited information about the conversion of HER2 subtypes between primary tumor and recurrent disease. Methods This retrospective study included women with BC at the University Medical Centre Wuerzburg from 1998 to 2021. Data were retrieved from patients' records. HER2 evolution from primary diagnosis to the first relapse and the development of secondary metastases was investigated. Results In the HR-positive subgroup without HER2 overexpression, HER2-low expression in primary BC was 56.7 vs. 14.6% in the triple-negative subgroup (p < 0.000). In the cohort of the first relapse, HER2-low represented 64.1% of HR-positive vs. 48.2% of the triple-negative cohort (p = 0.03). In patients with secondary metastases, HER2-low was 75.6% vs. 50% in the triple negative subgroup (p = 0.10). The subgroup of HER2-positive breast cancer patients numerically increased in the course of disease; the HER2-negative overall cohort decreased. A loss of HER2 expression from primary BC to the first relapse correlated with a better OS (p = 0.018). No clinicopathological or therapeutic features could be identified as potential risk factors for HER2 conversion. Conclusion HER2 expression is rising during the progression of BC disease. In view of upcoming therapeutical options, the re-analysis of newly developed metastasis will become increasingly important. KW - breast cancer KW - HER2 conversion KW - HER2-low KW - trastuzumab deruxtecan KW - HER2 targeted therapy KW - trastuzumab Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-324068 VL - 149 IS - 8 ER - TY - JOUR A1 - An, Ran A1 - Strissel, Pamela L. A1 - Al-Abboodi, Majida A1 - Robering, Jan W. A1 - Supachai, Reakasame A1 - Eckstein, Markus A1 - Peddi, Ajay A1 - Hauck, Theresa A1 - Bäuerle, Tobias A1 - Boccaccini, Aldo R. A1 - Youssef, Almoatazbellah A1 - Sun, Jiaming A1 - Strick, Reiner A1 - Horch, Raymund E. A1 - Boos, Anja M. A1 - Kengelbach-Weigand, Annika T1 - An innovative arteriovenous (AV) loop breast cancer model tailored for cancer research JF - Bioengineering N2 - Animal models are important tools to investigate the pathogenesis and develop treatment strategies for breast cancer in humans. In this study, we developed a new three-dimensional in vivo arteriovenous loop model of human breast cancer with the aid of biodegradable materials, including fibrin, alginate, and polycaprolactone. We examined the in vivo effects of various matrices on the growth of breast cancer cells by imaging and immunohistochemistry evaluation. Our findings clearly demonstrate that vascularized breast cancer microtissues could be engineered and recapitulate the in vivo situation and tumor-stromal interaction within an isolated environment in an in vivo organism. Alginate–fibrin hybrid matrices were considered as a highly powerful material for breast tumor engineering based on its stability and biocompatibility. We propose that the novel tumor model may not only serve as an invaluable platform for analyzing and understanding the molecular mechanisms and pattern of oncologic diseases, but also be tailored for individual therapy via transplantation of breast cancer patient-derived tumors. KW - arteriovenous loop KW - breast cancer KW - animal model Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-278919 SN - 2306-5354 VL - 9 IS - 7 ER - TY - JOUR A1 - Völker, Hans-Ullrich A1 - Weigel, Michael A1 - Strehl, Annette A1 - Frey, Lea T1 - Levels of uPA and PAI-1 in breast cancer and its correlation to Ki67-index and results of a 21-multigene-array JF - Diagnostic Pathology N2 - Background: Conventional parameters including Ki67, hormone receptor and Her2/neu status are used for risk stratification for breast cancer. The serine protease urokinase plasminogen activator (uPA) and the plasminogen activator inhibitor type-1 (PAI-1) play an important role in tumour invasion and metastasis. Increased concentrations in tumour tissue are associated with more aggressive potential of the disease. Multigene tests provide detailed insights into tumour biology by simultaneously testing several prognostically relevant genes. With OncotypeDX\(^{®}\), a panel of 21 genes is tested by means of quantitative real-time polymerase chain reaction. The purpose of this pilot study was to analyse whether a combination of Ki67 and uPA/PAI-1 supplies indications of the result of the multigene test. Methods: The results of Ki67, uPA/PAI-1 and OncotypeDX\(^{®}\) were analysed in 25 breast carcinomas (luminal type, pT1/2, max pN1a, G2). A statistical and descriptive analysis was performed. Results: With a proliferation index Ki67 of < 14%, the recurrence score (RS) from the multigene test was on average in the low risk range, with an intermediate RS usually resulting if Ki67 was > 14%. Not elevated values of uPA and PAI-1 showed a lower rate of proliferation (average 8.5%) than carcinomas with an increase of uPA and/or PAI-1 (average 13.9%); p = 0.054, Student’s t-test. When Ki67 was > 14% and uPA and/or PAI-1 was raised, an intermediate RS resulted. These differences were significant when compared to cases with Ki67 < 14% with non-raised uPA/PAI-1 (p < 0.03, Student’s t-test). Without taking into account the proliferative activity, an intermediate RS was also verifiable if both uPA and PAI-1 showed raised values. Conclusion: A combination of the values Ki67 and uPA/PAI-1 tended to depict the RS to be expected. From this it can be deduced that an appropriate analysis of this parameter combination may be undertaken before the multigene test in routine clinical practice. The increasing cost pressure makes it necessary to base the implementation of a multigene test on ancillary variables and to potentially leave it out if not required in the event of a certain constellation of results (Ki67 raised, uPA and PAI-1 raised). KW - breast cancer KW - OncotypeDX\(^{®}\) KW - uPA KW - multigene-array KW - PAI-1 Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-176960 VL - 13 IS - 67 ER - TY - JOUR A1 - Schlereth, Katharina A1 - Heyl, Charlotte A1 - Krampitz, Anna-Maria A1 - Mernberger, Marco A1 - Finkernagel, Florian A1 - Scharfe, Maren A1 - Jarek, Michael A1 - Leich, Ellen A1 - Rosenwald, Andreas A1 - Stiewe, Thorsten T1 - Characterization of the p53 Cistrome - DNA Binding Cooperativity Dissects p53's Tumor Suppressor Functions JF - PLOS Genetics N2 - p53 protects us from cancer by transcriptionally regulating tumor suppressive programs designed to either prevent the development or clonal expansion of malignant cells. How p53 selects target genes in the genome in a context-and tissue-specific manner remains largely obscure. There is growing evidence that the ability of p53 to bind DNA in a cooperative manner prominently influences target gene selection with activation of the apoptosis program being completely dependent on DNA binding cooperativity. Here, we used ChIP-seq to comprehensively profile the cistrome of p53 mutants with reduced or increased cooperativity. The analysis highlighted a particular relevance of cooperativity for extending the p53 cistrome to non-canonical binding sequences characterized by deletions, spacer insertions and base mismatches. Furthermore, it revealed a striking functional separation of the cistrome on the basis of cooperativity; with low cooperativity genes being significantly enriched for cell cycle and high cooperativity genes for apoptotic functions. Importantly, expression of high but not low cooperativity genes was correlated with superior survival in breast cancer patients. Interestingly, in contrast to most p53-activated genes, p53-repressed genes did not commonly contain p53 binding elements. Nevertheless, both the degree of gene activation and repression were cooperativity-dependent, suggesting that p53-mediated gene repression is largely indirect and mediated by cooperativity-dependently transactivated gene products such as CDKN1A, E2F7 and non-coding RNAs. Since both activation of apoptosis genes with non-canonical response elements and repression of pro-survival genes are crucial for p53's apoptotic activity, the cistrome analysis comprehensively explains why p53-induced apoptosis, but not cell cycle arrest, strongly depends on the intermolecular cooperation of p53 molecules as a possible safeguard mechanism protecting from accidental cell killing. KW - cell-cycle arrest KW - gene expression KW - breast cancer KW - human genome KW - transcriptional repression KW - consensus DNA KW - in-vivo KW - apoptosis KW - network KW - damage Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-127579 SN - 1553-7404 VL - 9 IS - 8 ER - TY - THES A1 - Flegler, Katharina T1 - Untersuchung der Expression von Knochensialoprotein (BSP) an Gewebe von Knochenmetastasen mittels Immunhistologie : Vergleich eines Antikörpers gegen nicht-glykosyliertes BSP mit einem Antikörper gegen glykosyliertes BSP T1 - Expression of bone sialoprotein (BSP) in bone metastases : antibodies against normal BSP compared to antibodies against BSP which bind epitopes that are incomplete in their posttranslational glycosylation N2 - Knochensialoprotein (BSP) ist ein Protein der extrazellulären Matrix im Knochen und mineralisierten Geweben, wird aber auch von verschiedenen Tumorzellen exprimiert (Bellahcene et al., 1994, 1997, 1998). Dies ist assoziiert mit einer schlechten Prognose und einem erhöhten Risiko für eine spätere Entwicklung von Knochenmetastasen. Diel et al. (1999) konnte zeigen, dass ein erhöhter Serum-BSP-Wert bei Patientinnen mit Mammakarzinom zu einem gehäuften Auftreten von Knochenmetastasen im Laufe der Erkrankung führt. BSP scheint ein Marker für die Entstehung von Knochenmetastasen zu sein. In der Literatur ist ein Antikörper beschrieben, der ein Epitop des BSP erkennt, welches im BSP aus Tumorzellen nicht glykosyliert ist, im BSP aus mineralisiertem Gewebe allerdings schon (Armbruster et al., 2009). Im Tiermodell konnte gezeigt werden, dass Knochenmetastasen verhindert werden können bei gleichzeitiger Gabe von Tumorzellen und Antikörpern gegen BSP beziehungsweise, dass bei vorhandenen Knochenmetastasen eine Behandlung der Tiere mit einem Anti-BSP-Antikörper die Metastasen zurückbildet (Bäuerle et al., 2005, 2006). In der aktuellen Arbeit wird die Expression von BSP an menschlichem Gewebe von Knochenmetastasen mit unterschiedlichen Primärtumoren mittels Immunhistochemie untersucht. Insgesamt wurden 35 Fälle von Knochenmetastasen mit Primärtumor eines Mammakarzinoms untersucht, wobei 22,9% eine BSP Expression aufweisen, davon 5,7% eine starke. Knochenmetastasen mit dem Primärtumor Prostatakarzinom sind mit 8 Fällen repräsentiert, wobei 75% positiv für BSP sind, davon 25% stark positiv. Die einzelnen Fälle zeigen eine starke BSP Expression im Stroma und eine schwache BSP Expression der Tumorzellen. Diese Ergebnisse des Antikörpers gegen normal glykosyliertes BSP wurden verglichen mit dem Antikörper gegen nicht glykosyliertes BSP. Der Nachweis von BSP in Tumorzellen zeigt dasselbe Ergebnis, BSP im Stroma wird durch den Antikörper gegen nicht- glykosyliertes BSP intensiver dargestellt. Daraus lässt sich folgern, dass der Antikörper gegen nicht- glykosyliertes BSP nicht spezifisch für die Isoform des BSP aus Tumorzellen ist, sondern gleichermaßen in der Routinediagnostik von BSP eingesetzt werden kann. Die Untersuchung könnte sogar darauf hinweisen, dass dieser Antikörper die nicht- glykosylierte Isoform im Stroma erkennt und damit bei Untersuchung des Stromas die bessere Alternative darstellt. N2 - Bone sialoprotein (BSP) is a bone matrix protein that is also expressed by breast cancer and prostate cancer cells (Bellahcene et al., 1994, 1997, 1998). The BSP expression in primary breast and prostate carcinomas is associated with a poor prognosis and an increased risk to develop bone metastases. Serum BSP was found to be a prognostic marker for the development of bone metastases (Diel et al. 1999). There are antibodies that specifically bind epitopes present in BSP produced in tumor cells, wherein the posttranslational glycosylation of BSP is incomplete in comparison with the posttranslational glycosylation of BSP produced in normal bone cells (Armbruster et al., 2009). In nude rats, incubation of breast cancer cells and anti-BSP antibodies prior to inoculation reduced the osteolytic lesion size. The treatment of bone metastases with an anti-BSP antibody resulted in a significantly smaller lesion size (Bäuerle et al., 2005, 2006). In the present study, 84 patient cases with bone metastases of different primary tumours were investigated by immunohistochemistry in order to assess the level of BSP and to compare two different anti-BSP antibodies. There are 35 cases of breast cancer bone metastases and 8 cases of prostate cancer bone metastases. BSP expression was found in 22, 9 % of all breast cancer bone metastases and 75% of all prostate cancer bone metastases. In nearly all cases a strong staining for BSP was found in stroma, a weak staining for BSP was observed in tumour cells. We compared antibodies against normal BSP with anti-BSP antibodies that bind epitopes that are incomplete in their posttranslational glycosylation. The expression of BSP in tumour cells was exactly the same, the expression of BSP in tumour stroma was different. A stronger staining was found with the antibodies that bind epitopes that are incomplete in their posttranslational glycosylation. In conclusion, these antibodies do not only stain for BSP produced by tumour cells. Both antibodies can be used for the detection of BSP. KW - Knochensialoprotein KW - Knochenmetastase KW - Mammakarzinom KW - bone sialoprotein KW - bone metastases KW - breast cancer Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-71642 ER - TY - THES A1 - Kieslich, Christian T1 - Numerische Chromosomen-Aberrationen im Carcinoma ductale in situ der Mamma unter besonderer Berücksichtigung neuerer Klassifikationen T1 - Numerical chromosomal aberrations in ductal carcinoma in situ of the female breast considering new classification systems N2 - Das duktale Carcinoma in situ (DCIS) der Mamma stellt eine Neoplasie mit sowohl heterogener Morphologie als auch variierendem biologischen Verhaltens dar. Dies führte in der Vergangenheit zur Etablierung zahlreicher pathohistologischer Klassifikationssysteme mit dem Ziel, das Risiko einer malignen Transformation in ein invasives Carcinom und die Wahrscheinlichkeit eines Lokalrezidivs nach Tumorektomie anhand histologischer Kriterien abzuschätzen. Zur Untersuchung solcher Klassifikationsparameter auf ihre Wichtigkeit sollte der genetische Hintergrund am Beispiel der chromosomalen Trisomie untersucht werden und mit diesen korreliert werden. Die Ergebnisse einer DNA-in situ-Hybridisierung an Paraffin-Material mit spezifischen Proben für die Chromosomen 1, 7, 8 und 18 zeigen, daß Trisomien in dieser Neoplasie ein häufiges Ereignis darstellen (56 Prozent aller Fälle) und daß diese mit den histologischen Parametern der Nekrose und einem hohen Kernatypiegrad korrelieren. Dieser Befund wird durch die Tatsache untermauert, daß solche Beziehungen sogar im gleichen Tumor gefunden werden, wenn dieser eine heterogene Morphologie aufwies. So läßt sich die große Bedeutung der Klassifikationsparameter Nekrose und Kern-Atypie auch durch die Ergebnisse der vorliegenden Arbeit unterstreichen. Eine Trisomie des Chromosoms 18 konnte nur in Fällen von einer Koinzidenz mit mikroinvasiven Herden detektiert werden. Dies deckt sich mit sämtlichen Angaben der Literatur, bei denen eine Trisomie 18 nie bei streng intraduktalem DCIS, sondern nur bei mikroinvasiven oder invasiven Mamma-Karzinomen gefunden wurde. Folglich wäre es wichtig, mit weiteren Untersuchungen die Bedeutung dieser Aberration im Invasionsgeschehen und in der Diagnosestellung einer Mikroinvasion des DCIS zu analysieren. N2 - Ductal carcinomata in situ (DCIS) of the female breast are heterogeneous in respect to their morphology and biology. Due to the local transition of some DCIS into invasive carcinoma, DCIS provides a suitable model to correlate morphologic features with genetic events underlying this malignant transformation. A possible relationship between histological and biological classification parameters of DCIS and the incidence of numerical chromosomal aberrations has been analyzed. Paraffin sections were investigated by in-situ-hybridization using specific DNA probes for chromosome 1,7, 8 and 18. Aneusomy was present in 56 per cent of DCIS and absent in the normal breast tissues. No correlation between aneusomy and growth pattern (comedo, clinging, cribriform, papillary, apocrine or intracystic) was observed. However, aneusomy was significantly associated with high nuclear grade, the presence of comedo-necrosis and microinvasion. Aneusomy 18 occured exclusively in 3 of 5 cases with microinvasive carcinoma and only in combination with trisomy 1, 7 and 8. This may argue for an involvement of aneusomy 18 in the transition from benign to malignant breast neoplasm. In new classification systems of DCIS the histological parameters necrosis and high nuclear grade were favored because of their clinical relevance. The present data support these findings as were able to link these histological parameters with cytogenetic events. KW - DCIS KW - Trisomie KW - in-situ-Hybridisierung KW - Klassifikation KW - Pathohistologie KW - Brustkrebs KW - DCIS KW - trisomy KW - aneusomy KW - in-situ-hybridization KW - classification KW - pathohistology KW - breast cancer Y1 - 2000 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-1180443 ER -