@article{StanglRauchRauhetal.2021, author = {Stangl, Stephanie and Rauch, Sebastian and Rauh, J{\"u}rgen and Meyer, Martin and M{\"u}ller-Nordhorn, Jacqueline and Wildner, Manfred and W{\"o}ckel, Achim and Heuschmann, Peter U.}, title = {Disparities in Accessibility to Evidence-Based Breast Cancer Care Facilities by Rural and Urban Areas in Bavaria, Germany}, series = {Cancer}, volume = {127}, journal = {Cancer}, number = {13}, doi = {10.1002/cncr.33493}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-239854}, pages = {2319 -- 2332}, year = {2021}, abstract = {Background Breast cancer (BC), which is most common in elderly women, requires a multidisciplinary and continuous approach to care. With demographic changes, the number of patients with chronic diseases such as BC will increase. This trend will especially hit rural areas, where the majority of the elderly live, in terms of comprehensive health care. Methods Accessibility to several cancer facilities in Bavaria, Germany, was analyzed with a geographic information system. Facilities were identified from the national BC guideline and from 31 participants in a proof-of-concept study from the Breast Cancer Care for Patients With Metastatic Disease registry. The timeframe for accessibility was defined as 30 or 60 minutes for all population points. The collection of address information was performed with different sources (eg, a physician registry). Routine data from the German Census 2011 and the population-based Cancer Registry of Bavaria were linked at the district level. Results Females from urban areas (n = 2,938,991 [ie, total of females living in urban areas]) had a higher chance for predefined accessibility to the majority of analyzed facilities in comparison with females from rural areas (n = 3,385,813 [ie, total number of females living in rural areas]) with an odds ratio (OR) of 9.0 for cancer information counselling, an OR of 17.2 for a university hospital, and an OR of 7.2 for a psycho-oncologist. For (inpatient) rehabilitation centers (OR, 0.2) and genetic counselling (OR, 0.3), women from urban areas had lower odds of accessibility within 30 or 60 minutes. Conclusions Disparities in accessibility between rural and urban areas exist in Bavaria. The identification of underserved areas can help to inform policymakers about disparities in comprehensive health care. Future strategies are needed to deliver high-quality health care to all inhabitants, regardless of residence.}, language = {en} } @article{HerbertWoeckelKreienbergetal.2021, author = {Herbert, S. L. and W{\"o}ckel, A. and Kreienberg, R. and K{\"u}hn, T. and Flock, F. and Felberbaum, R. and Janni, W. and Curtaz, C. and Kiesel, M. and St{\"u}ber, T. and Diessner, J. and Salmen, J. and Schwentner, L. and Fink, V. and Bekes, I. and Leinert, E. and Lato, K. and Polasik, A. and Schochter, F. and Singer, S.}, title = {To which extent do breast cancer survivors feel well informed about disease and treatment 5 years after diagnosis?}, series = {Breast Cancer Research and Treatment}, volume = {185}, journal = {Breast Cancer Research and Treatment}, organization = {BRENDA study group}, issn = {0167-6806}, doi = {10.1007/s10549-020-05974-y}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-232356}, pages = {677-684}, year = {2021}, abstract = {Objective In this study, we investigated to which extent patients feel well informed about their disease and treatment, which areas they wish more or less information and which variables are associated with a need for information about the disease, medical tests and treatment. Methods In a German multi-centre prospective study, we enrolled 759 female breast cancer patients at the time of cancer diagnosis (baseline). Data on information were captured at 5 years after diagnosis with the European Organisation for Research and Treatment of Cancer (EORTC) Information Module (EORTC QLQ-INFO24). Good information predictors were analysed using linear regression models. Results There were 456 patients who participated at the 5-year follow-up. They reported to feel well informed about medical tests (mean score 78.5) and the disease itself (69.3) but relatively poorly about other services (44.3) and about different places of care (31.3). The survivors expressed a need for more information concerning: side effects and long-term consequences of therapy, more information in general, information about aftercare, prognosis, complementary medicine, disease and therapy. Patients with higher incomes were better informed about medical tests (β 0.26, p 0.04) and worse informed with increasing levels of fear of treatment (β - 0.11, p 0.02). Information about treatment was reported to be worse by survivors > 70 years old (β -0.34, p 0.03) and by immigrants (β -0.11, p 0.02). Survivors who had received additional written information felt better informed about disease, medical tests, treatment and other services (β 0.19/0.19/0.20/0.25; each p < 0.01). Conclusion Health care providers have to reconsider how and what kind of information they provide. Providing written information, in addition to oral information, may improve meeting those information needs.}, language = {en} } @article{DiessnerWischnewskyBlettneretal.2016, author = {Diessner, Joachim and Wischnewsky, Manfred and Blettner, Maria and H{\"a}usler, Sebastian and Janni, Wolfgang and Kreienberg, Rolf and Stein, Roland and St{\"u}ber, Tanja and Schwentner, Lukas and Bartmann, Catharina and W{\"o}ckel, Achim}, title = {Do Patients with Luminal A Breast Cancer Profit from Adjuvant Systemic Therapy? A Retrospective Multicenter Study}, series = {PLoS ONE}, volume = {11}, journal = {PLoS ONE}, number = {12}, doi = {10.1371/journal.pone.0168730}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-178217}, year = {2016}, abstract = {Background Luminal A breast cancers respond well to anti-hormonal therapy (HT), are associated with a generally favorable prognosis and constitute the majority of breast cancer subtypes. HT is the mainstay of treatment of these patients, accompanied by an acceptable profile of side effects, whereas the added benefit of chemotherapy (CHT), including anthracycline and taxane-based programs, is less clear-cut and has undergone a process of critical revision. Methods In the framework of the BRENDA collective, we analyzed the benefits of CHT compared to HT in 4570 luminal A patients (pts) with primary diagnosis between 2001 and 2008. The results were adjusted by nodal status, age, tumor size and grading. Results There has been a progressive reduction in the use of CHT in luminal A patients during the last decade. Neither univariate nor multivariate analyses showed any statistically significant differences in relapse free survival (RFS) with the addition of CHT to adjuvant HT, independent of the nodal status, age, tumor size or grading. Even for patients with more than 3 affected lymph nodes, there was no significant difference (univariate: p = 0.865; HR 0.94; 95\% CI: 0.46-1.93; multivariate: p = 0.812; HR 0.92; 95\% CI: 0.45-1.88). Conclusions The addition of CHT to HT provides minimal or no clinical benefit at all to patients with luminal A breast cancer, independent of the RFS-risk. Consequently, risk estimation cannot be the initial step in the decisional process. These findings-that are in line with several publications-should encourage the critical evaluation of applying adjuvant CHT to patients with luminal A breast cancer.}, language = {en} } @article{EndresKneitzOrthetal.2016, author = {Endres, Marcel and Kneitz, Susanne and Orth, Martin F. and Perera, Ruwan K. and Zernecke, Alma and Butt, Elke}, title = {Regulation of matrix metalloproteinases (MMPs) expression and secretion in MDA-MB-231 breast cancer cells by LIM and SH3 protein 1 (LASP1)}, series = {Oncotarget}, volume = {7}, journal = {Oncotarget}, number = {39}, doi = {10.18632/oncotarget.11720}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-176920}, pages = {64244-64259}, year = {2016}, abstract = {The process of tumor invasion requires degradation of extracellular matrix by proteolytic enzymes. Cancer cells form protrusive invadopodia, which produce and release matrix metalloproteinases (MMPs) to degrade the basement membrane thereby enabling metastasis. We investigated the effect of LASP1, a newly identified protein in invadopodia, on expression, secretion and activation of MMPs in invasive breast tumor cell lines. By analyzing microarray data of in-house generated control and LASP1-depleted MDA-MB-231 breast cancer cells, we observed downregulation of MMP1, -3 and -9 upon LASP1 depletion. This was confirmed by Western blot analysis. Conversely, rescue experiments restored in part MMP expression and secretion. The regulatory effect of LASP1 on MMP expression was also observed in BT-20 breast cancer cells as well as in prostate and bladder cancer cell lines. In line with bioinformatic FunRich analysis of our data, which mapped a high regulation of transcription factors by LASP1, public microarray data analysis detected a correlation between high LASP1 expression and enhanced c-Fos levels, a protein that is part of the transcription factor AP-1 and known to regulate MMP expression. Compatibly, in luciferase reporter assays, AP-1 showed a decreased transcriptional activity after LASP1 knockdown. Zymography assays and Western blot analysis revealed an additional promotion of MMP secretion into the extracellular matrix by LASP1, thus, most likely, altering the microenvironment during cancer progression. The newly identified role of LASP1 in regulating matrix degradation by affecting MMP transcription and secretion elucidated the migratory potential of LASP1 overexpressing aggressive tumor cells in earlier studies.}, language = {en} } @article{ReinersSchneiderPlatonovaetal.2020, author = {Reiners, Christoph and Schneider, Rita and Platonova, Tamara and Fridman, Mikhail and Malzahn, Uwe and M{\"a}der, Uwe and Vrachimis, Alexis and Bogdanova, Tatiana and Krajewska, Jolanta and Elisei, Rossella and Vaisman, Fernanda and Mihailovic, Jasna and Costa, Gracinda and Drozd, Valentina}, title = {Breast Cancer After Treatment of Differentiated Thyroid Cancer With Radioiodine in Young Females: What We Know and How to Investigate Open Questions. Review of the Literature and Results of a Multi-Registry Survey}, series = {Frontiers in Endocrinology}, volume = {11}, journal = {Frontiers in Endocrinology}, issn = {1664-2392}, doi = {10.3389/fendo.2020.00381}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-207766}, year = {2020}, abstract = {Published studies on the risk of radiation-induced second primary malignancy (SPM) after radioiodine treatment (RAI) of differentiated thyroid cancer (DTC) refer mainly to patients treated as middle-aged or older adults and are not easily generalizable to those treated at a younger age. Here we review available literature on the risk of breast cancer as an SPM after RAI of DTC with a focus on females undergoing such treatment in childhood, adolescence, or young adulthood. Additionally, we report the results of a preliminary international survey of patient registries from academic tertiary referral centers specializing in pediatric DTC. The survey sought to evaluate the availability of sufficient patient data for a potential international multicenter observational case-control study of females with DTC given RAI at an early age. Our literature review identified a bi-directional association of DTC and breast cancer. The general breast cancer risk in adult DTC survivors is low, ~2\%, slightly higher in females than in males, but presumably lower, not higher, in those diagnosed as children or adolescents than in those diagnosed at older ages. RAI presumably does not substantially influence breast cancer risk after DTC. However, data from patients given RAI at young ages are sparse and insufficient to make definitive conclusions regarding age dependence of the risk of breast cancer as a SPM after RAI of DTC. The preliminary analysis of data from 10 thyroid cancer registries worldwide, including altogether 6,449 patients given RAI for DTC and 1,116 controls, i.e., patients not given RAI, did not show a significant increase of breast cancer incidence after RAI. However, the numbers of cases and controls were insufficient to draw statistically reliable conclusions, and the proportion of those receiving RAI at the earliest ages was too low.In conclusion, a potential international multicenter study of female patients undergoing RAI of DTC as children, adolescents, or young adults, with a sufficient sample size, is feasible. However, breast cancer screening of a larger cohort of DTC patients is not unproblematic for ethical reasons, due to the likely, at most slightly, increased risk of breast cancer post-RAI and the expected ~10\% false-positivity rate which potentially produced substantial "misdiagnosis."}, language = {en} } @article{WolterHanselmannPattschulletal.2017, author = {Wolter, Patrick and Hanselmann, Steffen and Pattschull, Grit and Schruf, Eva and Gaubatz, Stefan}, title = {Central spindle proteins and mitotic kinesins are direct transcriptional targets of MuvB, B-MYB and FOXM1 in breast cancer cell lines and are potential targets for therapy}, series = {Oncotarget}, volume = {8}, journal = {Oncotarget}, number = {7}, doi = {10.18632/oncotarget.14466}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-171851}, pages = {11160-11172}, year = {2017}, abstract = {The MuvB multiprotein complex, together with B-MYB and FOXM1 (MMB-FOXM1), plays an essential role in cell cycle progression by regulating the transcription of genes required for mitosis and cytokinesis. In many tumors, B-MYB and FOXM1 are overexpressed as part of the proliferation signature. However, the transcriptional targets that are important for oncogenesis have not been identified. Given that mitotic kinesins are highly expressed in cancer cells and that selected kinesins have been reported as target genes of MMB-FOXM1, we sought to determine which mitotic kinesins are directly regulated by MMB-FOXM1. We demonstrate that six mitotic kinesins and two microtubule-associated non-motor proteins (MAPs) CEP55 and PRC1 are direct transcriptional targets of MuvB, B-MYB and FOXM1 in breast cancer cells. Suppression of KIF23 and PRC1 strongly suppressed proliferation of MDA-MB-231 cells. The set of MMB-FOXM1 regulated kinesins genes and 4 additional kinesins which we referred to as the mitotic kinesin signature (MKS) is linked to poor outcome in breast cancer patients. Thus, mitotic kinesins could be used as prognostic biomarker and could be potential therapeutic targets for the treatment of breast cancer.}, language = {en} } @article{SchererBauerSchmausetal.2016, author = {Scherer, Sandra D. and Bauer, Jochen and Schmaus, Anja and Neumaier, Christian and Herskind, Carsten and Veldwijk, Marlon R. and Wenz, Frederik and Sleeman, Jonathan P.}, title = {TGF-β1 Is Present at High Levels in Wound Fluid from Breast Cancer Patients Immediately Post-Surgery, and Is Not Increased by Intraoperative Radiation Therapy (IORT)}, series = {PLoS ONE}, volume = {11}, journal = {PLoS ONE}, number = {9}, doi = {10.1371/journal.pone.0162221}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-166811}, pages = {e0162221}, year = {2016}, abstract = {In patients with low-risk breast cancer, intraoperative radiotherapy (IORT) during breast-conserving surgery is a novel and convenient treatment option for delivering a single high dose of irradiation directly to the tumour bed. However, edema and fibrosis can develop after surgery and radiotherapy, which can subsequently impair quality of life. TGF-β is a strong inducer of the extracellular matrix component hyaluronan (HA). TGF-β expression and HA metabolism can be modulated by irradiation experimentally, and are involved in edema and fibrosis. We therefore hypothesized that IORT may regulate these factors.Wound fluid (WF) draining from breast lumpectomy sites was collected and levels of TGF-β1 and HA were determined by ELISA. Proliferation and marker expression was analyzed in primary lymphatic endothelial cells (LECs) treated with recombinant TGF-β or WF. Our results show that IORT does not change TGF-β1 or HA levels in wound fluid draining from breast lumpectomy sites, and does not lead to accumulation of sHA oligosaccharides. Nevertheless, concentrations of TGF-β1 were high in WF from patients regardless of IORT, at concentrations well above those associated with fibrosis and the suppression of LEC identity. Consistently, we found that TGF-β in WF is active and inhibits LEC proliferation. Furthermore, all three TGF-β isoforms inhibited LEC proliferation and suppressed LEC marker expression at pathophysiologically relevant concentrations. Given that TGF-β contributes to edema and plays a role in the regulation of LEC identity, we suggest that inhibition of TGF-β directly after surgery might prevent the development of side effects such as edema and fibrosis.}, language = {en} } @article{VoelkerWeigelStrehletal.2018, author = {V{\"o}lker, Hans-Ullrich and Weigel, Michael and Strehl, Annette and Frey, Lea}, title = {Levels of uPA and PAI-1 in breast cancer and its correlation to Ki67-index and results of a 21-multigene-array}, series = {Diagnostic Pathology}, volume = {13}, journal = {Diagnostic Pathology}, number = {67}, doi = {10.1186/s13000-018-0737-5}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-176960}, year = {2018}, abstract = {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).}, language = {en} } @article{BartmannJanakiRamanFloeteretal.2018, author = {Bartmann, Catharina and Janaki Raman, Sudha R. and Fl{\"o}ter, Jessica and Schulze, Almut and Bahlke, Katrin and Willingstorfer, Jana and Strunz, Maria and W{\"o}ckel, Achim and Klement, Rainer J. and Kapp, Michaela and Djuzenova, Cholpon S. and Otto, Christoph and K{\"a}mmerer, Ulrike}, title = {Beta-hydroxybutyrate (3-OHB) can influence the energetic phenotype of breast cancer cells, but does not impact their proliferation and the response to chemotherapy or radiation}, series = {Cancer \& Metabolism}, volume = {6}, journal = {Cancer \& Metabolism}, number = {8}, doi = {10.1186/s40170-018-0180-9}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-175607}, year = {2018}, abstract = {Background: Ketogenic diets (KDs) or short-term fasting are popular trends amongst supportive approaches for cancer patients. Beta-hydroxybutyrate (3-OHB) is the main physiological ketone body, whose concentration can reach plasma levels of 2-6 mM during KDs or fasting. The impact of 3-OHB on the biology of tumor cells described so far is contradictory. Therefore, we investigated the effect of a physiological concentration of 3 mM 3-OHB on metabolism, proliferation, and viability of breast cancer (BC) cells in vitro. Methods: Seven different human BC cell lines (BT20, BT474, HBL100, MCF-7, MDA-MB 231, MDA-MB 468, and T47D) were cultured in medium with 5 mM glucose in the presence of 3 mM 3-OHB at mild hypoxia (5\% oxygen) or normoxia (21\% oxygen). Metabolic profiling was performed by quantification of the turnover of glucose, lactate, and 3-OHB and by Seahorse metabolic flux analysis. Expression of key enzymes of ketolysis as well as the main monocarboxylic acid transporter MCT2 and the glucose-transporter GLUT1 was analyzed by RT-qPCR and Western blotting. The effect of 3-OHB on short- and long-term cell proliferation as well as chemo- and radiosensitivity were also analyzed. Results: 3-OHB significantly changed the oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) in BT20 cells resulting in a more oxidative energetic phenotype. MCF-7 and MDA-MB 468 cells had increased ECAR only in response to 3-OHB, while the other three cell types remained uninfluenced. All cells expressed MCT2 and GLUT1, thus being able to uptake the metabolites. The consumption of 3-OHB was not strongly linked to mRNA overexpression of key enzymes of ketolysis and did not correlate with lactate production and glucose consumption. Neither 3-OHB nor acetoacetate did interfere with proliferation. Further, 3-OHB incubation did not modify the response of the tested BC cell lines to chemotherapy or radiation. Conclusions: We found that a physiological level of 3-OHB can change the energetic profile of some BC cell lines. However, 3-OHB failed to influence different biologic processes in these cells, e.g., cell proliferation and the response to common breast cancer chemotherapy and radiotherapy. Thus, we have no evidence that 3-OHB generally influences the biology of breast cancer cells in vitro.}, language = {en} } @article{ThibaudeauTaubenbergerTheodoropoulosetal.2015, author = {Thibaudeau, Laure and Taubenberger, Anna V. and Theodoropoulos, Christina and Holzapfel, Boris M. and Ramuz, Olivier and Straub, Melanie and Hutmacher, Dietmar W.}, title = {New mechanistic insights of integrin β1 in breast cancer bone colonization}, series = {Oncotarget}, volume = {6}, journal = {Oncotarget}, number = {1}, doi = {10.18632/oncotarget.2788}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-175432}, pages = {332-344}, year = {2015}, abstract = {Bone metastasis is a frequent and life-threatening complication of breast cancer. The molecular mechanisms supporting the establishment of breast cancer cells in the skeleton are still not fully understood, which may be attributed to the lack of suitable models that interrogate interactions between human breast cancer cells and the bone microenvironment. Although it is well-known that integrins mediate adhesion of malignant cells to bone extracellular matrix, their role during bone colonization remains unclear. Here, the role of β1 integrins in bone colonization was investigated using tissue-engineered humanized in vitro and in vivo bone models. In vitro, bone-metastatic breast cancer cells with suppressed integrin β1 expression showed reduced attachment, spreading, and migration within human bone matrix compared to control cells. Cell proliferation in vitro was not affected by β1 integrin knockdown, yet tumor growth in vivo within humanized bone microenvironments was significantly inhibited upon β1 integrin suppression, as revealed by quantitative in/ex vivo fluorescence imaging and histological analysis. Tumor cells invaded bone marrow spaces in the humanized bone and formed osteolytic lesions; osteoclastic bone resorption was, however, not reduced by β1 integrin knockdown. Taken together, we demonstrate that β1 integrins have a pivotal role in bone colonization using unique tissue-engineered humanized bone models.}, language = {en} }