Background: High mobility group A proteins are involved in chromatin remodeling, thereby influencing multiple fundamental biological processes. HMGA2 has been linked to oncogenic traits among a variety of malignancies. Objective: To determine the prognostic implications of subcellular distribution patterns of HMGA2 in breast cancer. Methods: Nuclear and cytoplasmic HMGA2 was evaluated in 342 breast cancer specimens and matched with clinico-pathological parameters. Results: Overall and cytoplasmic, but not nuclear, levels of HMGA2 correlated with better survival prognoses in our collective (hazard ratio (HR) 0.34, P = 0.001 and HR 0.34, P < 0.001, respectively). The protective effect of cytoplasmic HMGA2 persisted in the Luminal A and triple negative breast cancer subgroups. Evaluating Luminal A and B subgroups jointly, only cytoplasmic, but not overall or nuclear HMGA2 levels were associated with better survival (HR 0.42, 95% confidence interval 0.21, 0.86, P = 0.017), irrespective of tumor size and node status. The addition of HMGA2 overall and cytoplasmic scores strengthened the prognostic selectivity in a model of conventional breast cancer risk factors. No predictive significance with regard to endocrine or chemoendocrine therapies was observed. Conclusion: Unexpectedly, we found a favorable survival probability upon overall levels of HMGA2 in our breast cancer collective, which was predominantly determined by the presence of HMGA2 in the cytoplasm.

Objective High mobility group A proteins are involved in chromatin remodelling, thereby influencing multiple fundamental biological processes. HMGA2 has been linked to oncogenic traits among a variety of malignancies, but little is known about the value of extra-nuclear HMGA2. Therefore, we determined the prognostic implications of subcellular distribution patterns of HMGA2 in breast cancer.

Upon ligand binding, plasma membrane–located TNF-related apoptosis-inducing ligand (TRAIL)–receptors 1 and 2 induce apoptosis as well as cancer-promoting signaling in cancer cells. TRAIL-R3 and TRAIL-R4 are believed to negatively regulate TRAIL-mediated apoptosis. Intracellular localization of TRAIL-receptors, as observed in many tumor cells, has been associated with oncogenic features, which are distinct from membrane-associated TRAIL-R signaling. Here, analyzing a panel of 354 breast cancer specimens, we found that an unfavorable outcome correlating with cancer-promoting properties of TRAIL-R1, TRAIL-R2, and TRAIL-R4 was most significantly defined by their intracellular distribution and mutual co-expression. A nuclear or cytoplasmic heterogeneous expression pattern correlated with markedly decreased overall survival and discriminated high-risk breast cancer patients from low-risk patients with a homogeneous distribution of expression, i.e., nuclear and cytoplasmic expression. The homogeneous TRAIL-R expression was associated with favorable breast cancer surrogate markers corresponding with excellent survival prognoses at 5 years after diagnosis (hazard ratio, 0.043) and over the complete course of follow-up (hazard ratio, 0.098; both p < 0.001). No associations with specific intrinsic breast cancer subtypes were found. Our data suggest that the determination of intracellular co-expression patterns of TRAIL-R1, TRAIL-R2, and TRAIL-R4 provides an innovative and robust method for risk stratification in breast cancer patients beyond conventional prognostic markers.

The numerous side effects of chemotherapy in patients with breast cancer are well known. However, the precise effects of chemotherapy on ovarian function in premenopausal women are poorly investigated. The patients are at risk of developing sexual hormone deficiency and impaired fertility. This prospective cohort study addresses predictive parameters of ovarian reserve after chemotherapy.

BACKGROUND AND OBJECTIVE: Progress in endoscopic surgery in the past few decades has led to the application of 3-dimensional (3D) procedures in operating rooms. This permits patient- and surgeon-friendly operations and also maximizes the superiority of laparoscopy over laparotomy. In this study, we compare 2-dimensional (2D) and 3D endoscopy techniques with regard to time, efficiency, optics, and handling by users with different degrees of experience at 4 difficulty levels. DESIGN: A randomized controlled trial on a pelvitrainer in objectively graded surgical steps for students and postgraduates. SETTING: The trials took place at the Kiel School of Gynaecological Endoscopy, a training unit of the Kiel University Department of Obstetrics and Gynecology, a tertiary academic medical center. PARTICIPANTS: The 277 study participants, divided into students, residents, and specialists, worked on pelvitrainers with 2 different optical systems, the 2D full HD and the 3D mode. The following 4 exercises were performed with each optical system: (1) grasping and transferring of pins, (2) cutting predetermined marks, (3) vaginal closure with prevention of prolapse, and (4) sacrocolpopexy. The duration and success of the tasks were measured and compared. A self-assessment questionnaire was completed by the participants. RESULTS: Overall, the 3D-system permitted a greater improvement in working speed, superior optical visualization, and better endoscopic handling in all groups, independent of surgical experience. All students improved in speed (exercises: 1-3) and made significantly fewer mistakes (exercise 2) on 3D compared with 2D. Residents made progress in time (exercises: 1-4) and task performance (exercise 3). Specialists improved significantly in the more challenging tasks 3 and 4. Subjectively, 68.8% of participants preferred 3D for performing laparoscopy. CONCLUSION: Systematic training programs on pelvitrainers can improve endoscopic skills not only in beginners but also in experienced surgeons. The 3D system offered distinct advantages over 2D imaging and was well arfrpted by surgeons. (C) 2017 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.

Tumor-infiltrating lymphocytes (TILs) in breast cancer are a key representative of the tumor immune microenvironment and have been shown to provide prognostic and predictive biomarkers. The extent of lymphocytic infiltration in tumor tissues can be assessed by evaluating hematoxylin and eosin (H&E)-stained tumor sections. We investigated tissue microarrays of 31 invasive breast cancer patients, looking at quantity and topological distribution of CD3+, CD8+, CD20+, Ki67+, FoxP3+ TILs and CD3+/FoxP3+, CD8+/FoxP3+ cell ratios. We separately evaluated TILs at the invasive edge and at the center of the tumor, to find any clinical implications of tumor heterogeneity. No statistically significant difference was found in quantity and distribution of both TIL subsets and TIL ratios, by comparing patients who suffered from a local or distant recurrence of the tumor (relapse group: 13 patients) with patients not showing cancer relapse (non-relapse group: 18 patients). In the whole sample, we observed three main statistically significant positive correlations: (1) between CD3+ and CD8+ T-cells; (2) between FoxP3+ and Ki67+ lymphocyte infiltration; (3) between CD3+/FoxP3+ cell ratio (C3FR) and CD8+/FoxP3+ cell ratio (C8FR). Tumor heterogeneity and stronger positive TIL associations were found in the non-relapse group, where both CD3–CD8 and FoxP3-Ki67 inter-correlations were found to be significant at the center of the tumor, while the correlation between C3FR and C8FR was significant at the invasive edge. No correlations between TIL subsets were detected in the relapse group. Our findings suggest the existence of stronger inter-subtype lymphocytic networks in invasive breast cancer not showing recurrence. Further evaluations of clinical and topological correlations between and within TIL subsets are needed, in addition to the assessment of TIL quantification and distribution, in order to follow up on whether morphological evaluation of TILs might reveal the underlying lymphocytic functional connectivity and help relapse prediction.

PURPOSE:Tumor surgery is aimed at complete resection of the lesion while ensuring a sufficient tumor-specific safety distance. Nevertheless, in many cases the most peripheral part - the invasion front - remains in situ. Tumor cells at the tumor margin have been reported to lose their epithelial properties and acquire features of mesenchymal cells. The process of epithelial-to-mesenchymal transition (EMT) is believed to be of prime importance for tissue and vessel invasion. Furthermore, the detection of tumor-infiltrating lymphocytes in the microenvironment of breast cancer might serve as a reliable prognostic marker. METHODS:We investigated tissue microarrays of 352 breast cancer patients with regard to the presence and distribution of the EMT factor Snail, and the presence of FoxP3, CD3 and CD8 in the immune microenvironment. RESULTS:The expression of the transcription factor Snail is strongly associated with longer disease-free and overall survival. The presence of CD3, CD8 or FoxP3 is associated with a better outcome, although statistically significant results were noted only for FoxP3. The prognostic significance of FoxP3 and Snail were also proven in multivariate analysis. CONCLUSIONS:Based on previous studies concerning the intratumoral heterogeneity of EMT, our results suggest that Snail and FoxP3 are possible prognostic markers for breast cancer. The diverse presence of lymphocytes in the tumor microenvironment (CD3 and CD8) was confirmed. Although the importance of these markers is known, their specific role in tumor invasion and metastasis as well as their hierarchical organization in these tumors remain unclear.

Mdm2 (Human mouse double minute 2) is an important opponent of the tumor suppressor p53. The G/G variant of SNP309 in the MDM2 promoter can increase Mdm2 mRNA/protein expression and is associated with an increased risk and earlier onset of different cancers especially in Asian populations. But the frequency and impact of the G/G variant has not been studied in Caucasian renal cell carcinoma (RCC) patients. Therefore, we analyzed an unselected German cohort of 197 consecutive RCC patients and detected the G/G variant in 18 (9.1%) patients, the G/T variant in 116 (58.9%) patients and the T/T variant in 63 (32.0%) patients. Studying the association between age at tumor onset and SNP309 genotypes, no correlation was detected in the entire RCC cohort or among the male RCC patients. However, the female G/G patients (median age 59.5 years) were diagnosed 13.5 years earlier than the T/T females (median age 73 years). Next, when separating all females into two groups at their median age (68 years), 7 patients and 1 patient with the G/G variant and 9 patients and 13 patients with the T/T variant were noted in these age groups (P = 0.024). To study the age dependency of tumor onset further, a second, age-selected cohort of 205 RCC patients was analyzed, which comprised especially young and old patients. Interestingly, the G/G type occurred more often at lower tumor stages and tumor grades compared with higher stages (P = 0.039 and P = 0.004, respectively). In females, the percentage of the G/G variant was only slightly higher in the younger age group, whereas in males, the percentage of the G/G variant was remarkably higher in the younger age group (19.4% vs. 8.0%). In summary, female Caucasian RCC patients with the MDM2 SNP 309 G/G variant showed a significantly earlier tumor onset than patients with the wildtype T/T genotype. Citation Format: Christine G. Stoehr, Robert Stoehr, Antonia Wenners, Arndt Hartmann, Simone Bertz, Verena Spath, Bernhard Walter, Kerstin Junker, Holger Moch, Raoul Hintze, Stefan Denzinger, Elisabeth E. Bond, Gareth L. Bond, Karen Bluemke, Katrin Weigelt, Verena Lieb, Elke Nolte, Paolo Fornara, Bernd Wullich, Sven Wach, Helge W. Taubert. Association of the G/G-SNP309 variant in the mdm2 gene with earlier tumor onset in female renal cell carcinoma patients. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3700.

The orphan G protein-coupled receptor GPR55 has been directly or indirectly related to basic alterations that drive malignant growth: uncontrolled cancer cell proliferation, sustained angiogenesis, and cancer cell adhesion and migration. However, little is known about the involvement of this receptor in metastasis. Here, we show that elevated GPR55 expression in human tumors is associated with the aggressive basal/triple-negative breast cancer population, higher probability to develop metastases, and therefore poor patient prognosis. Activation of GPR55 by its proposed endogenous ligand lysophosphatidylinositol confers pro-invasive features on breast cancer cells both in vitro and in vivo. Specifically, this effect is elicited by coupling to Gq/11 heterotrimeric proteins and the subsequent activation, through ERK, of the transcription factor ETV4/PEA3. Together, these data show that GPR55 promotes breast cancer metastasis, and supports the notion that this orphan receptor may constitute a new therapeutic target and potential biomarker in the highly aggressive triple-negative subtype.

Stromal fibroblasts influence tumor growth and progression. We evaluated two aldo–keto reductases, AKR1C1 and AKR1C2, in stromal fibroblasts and carcinoma cells as prognostic factors in primary human breast cancer. They are involved in intratumoral progesterone metabolism.

Abstract Background: Sideeffects of adjuvant chemotherapy on ovarian function are inadequately studied by now. Premenopausal women undergoing chemotherapy are at risk for sexual hormone deficiency and impaired fertility. This prospective cohort study searches for predictive parameters of ovarian reserve after chemotherapy. Methods: 51 premenopausal patients (average 38 years; 28-46 years) with primary breast cancer have been included. They all received neo- or adjuvant chemotherapy: anthracycline based "A"(FEC)(n= 18); anthracycline/taxane based "T"( TAC or FEC/Doc or EC/Pac)(n=30) or anthracycline- free "AF"(n=3). After chemotherapy patients received endocrine therapy (ET) for hormone receptor (HR) positive disease (tamoxifen (n=34) or goserelin/tamoxifen (n=7)). For HR negative disease (n=20) no ET was given. Before (visit 1) and 6, 12 and 24 months after initiation of chemotherapy (visit 2-4) age and chemotherapy related changes in hormone (LH, FSH, E2 and Anti-Muellerian hormone (AMH)) levels, antral follicle count and amenorrhea as parameters of endocrine function and fertility were assessed. Also quality of life (QL) and additional impact of parity, BMI and nicotine use on ovarian reserve were evaluated. Results: Antral follicle count is decreasing dramatically after chemotherapy and is not fully recovering after 2 years. Antral follicle count before and 1 year after chemotherapy are significantly correlated (p=0.012). Follicle count and age before chemotherapy are negatively correlated (p=0.004). At visit 4 the type of chemotherapy (A, T, AF) has no influence on antral follicle count or AMH levels. Tamoxifen is correlated with a significant decrease in follicle count (vs. no endocrine therapy) (p=0.039). Smoking is significantly detrimental on antral follicle count after 24 months (p=0.001). AMH levels at visits 2-4 are significantly correlated with levels at the 1 visit and are negatively correlated with age (p=0.032). Tamoxifen therapy has no impact on AMH levels. LH and FSH are increasing between visit 1 and 2 and decreasing at visits 3 and 4 (but stay above basic levels). At visit 4 LH is not and FSH is correlated with visit 1 levels (p=0.005). LH and FSH are correlated with age (p=0.0001) and are not influenced by type of chemotherapy or tamoxifen .E2 levels at visit 4 are not influenced by type of chemotherapy, but significantly decreased (p=0.003) by continued smoking. At visit 4 31/51 patients have stayed amenorrheic, 19 resumed their menstruation. This was not influenced by type of chemotherapy or age. Non- smokers are 13 times more likely to resume their menstruation (vs. smokers). Tamoxifen is correlated with a higher probability of permanent amenorrhea (p=0.058, n.s.). BMI, nicotine abuse, age, type of chemotherapy and tamoxifen have no influence on duration of amenorrhea. QL is significantly lower at visit 2, but recovers to basic values at visits 3 and 4. Conclusions: Our study contributes to a better prediction of ovarian reserve before chemotherapy. We suggest personalized counselling on fertility preserving measures before chemotherapy especially at higher age, with low AMH levels or low antral follicle counts. To stop smoking could enhance chances for ovarian preservation. Citation Format: Christoph Mundhenke, Antonia S Wenners, Jana Grambach, Juliane Koss, Ulrike von Hehn, Walter Jonat, Andreas G Schmutzler. Reduction of ovarian reserve in young early breast cancer patients: 24 months follow up of a prospective cohort trial [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-12-05.

BACKGROUND Pharmacological activation of cannabinoid receptors elicits antitumoral responses in different cancer models. However, the biological role of these receptors in tumor physio-pathology is still unknown. METHODS We analyzed CB2 cannabinoid receptor protein expression in two series of 166 and 483 breast tumor samples operated in the University Hospitals of Kiel, Tübingen, and Freiburg between 1997 and 2010 and CB2 mRNA expression in previously published DNA microarray datasets. The role of CB2 in oncogenesis was studied by generating a mouse line that expresses the human V-Erb-B2 Avian Erythroblastic Leukemia Viral Oncogene Homolog 2 (HER2) rat ortholog (neu) and lacks CB2 and by a variety of biochemical and cell biology approaches in human breast cancer cells in culture and in vivo, upon modulation of CB2 expression by si/shRNAs and overexpression plasmids. CB2-HER2 molecular interaction was studied by colocalization, coimmunoprecipitation, and proximity ligation assays. Statistical tests were two-sided. RESULTS We show an association between elevated CB2 expression in HER2+ breast tumors and poor patient prognosis (decreased overall survival, hazard ratio [HR] = 0.29, 95% confidence interval [CI] = 0.09 to 0.71, P = .009) and higher probability to suffer local recurrence (HR = 0.09, 95% CI = 0.049 to 0.54, P = .003) and to develop distant metastases (HR = 0.33, 95% CI = 0.13 to 0.75, P = .009). We also demonstrate that genetic inactivation of CB2 impairs tumor generation and progression in MMTV-neu mice. Moreover, we show that HER2 upregulates CB2 expression by activating the transcription factor ELK1 via the ERK cascade and that an increased CB2 expression activates the HER2 pro-oncogenic signaling at the level of the tyrosine kinase c-SRC. Finally, we show HER2 and CB2 form heteromers in cancer cells. CONCLUSIONS Our findings reveal an unprecedented role of CB2 as a pivotal regulator of HER2 pro-oncogenic signaling in breast cancer, and they suggest that CB2 may be a biomarker with prognostic value in these tumors.

Eduardo Pérez-Gómez, Clara Andradas, María M. Caffarel, Sandra Blasco-Benito, Elena García-Taboada, María Villa-Morales, Estefanía Moreno, Sigrid Hamann, Ester Martín-Villar, Juana M. Flores, Antonia Wenners, Ibrahim Alkatout, Wolfram Klapper, Christoph Röcken, Peter Bronsert, Elmar Stickeler, Annette Staebler, Maret Bauer, Norbert Arnold, Joaquim Soriano, Manuel Pérez-Martínez, Diego Megías, Gema Moreno-Bueno, Silvia Ortega-Gutiérrez, Marta Artola, Henar Vázquez-Villa, Miguel Quintanilla, José Fernández-Piqueras, Enric I. Canela, Peter J. McCormick, Manuel Guzmán and Cristina Sánchez

BACKGROUND Fibroblast growth factor-2 (FGF-2) supports tumor progression in breast cancer. FGF-2 signaling is modulated by heparan sulfate proteoglycans, such as syndecan-1 (CD138). The exact role of CD138 in ductal carcinoma in situ of the breast (DCIS) is still uncertain. Differential expression depending on grading could suggest a role for syndecan-1 during growth and tumor progression. MATERIALS AND METHODS Samples of 127 cases of breast DCIS associated with follow-up data were included. CD138 staining intensity, number of positive cells, intracellular and tissue localization were examined. RESULTS Median follow-up was 45.4 months and median recurrence-free survival (RFS) 86 months. Age, menopausal status and previous hormone replacement therapy had no significant influence on RFS. Smoking significantly influenced RFS (p=0.008). Endocrine therapy or radiotherapy did not improve RFS. Grading was not correlated with CD138 staining intensity, but was significantly associated with the percentage of CD138-positive cells (low-vs. high-grade, p=0.043). Estrogen receptor (ER) expression did not influence staining intensity of CD138 (p=0.247), but negatively correlated with the proportion of CD138-positive cells (p=0.032). Progesterone receptor (PR) expression significantly influenced the intensity of staining (p=0.010) and the percentage of CD138-positive cells (p=0.004); both were increased in PR-negative cases. CD138 staining intensity and percentage of positive cells did not correlate with RFS. Nuclear grade and syndecan-1 staining localization were significantly associated (p=0.001). ER-positive, and PR-positive DCIS more often exhibited membrane-bound syndecan-1 than ER- or PR-negative cases (p=0.001). Nuclear grade and tissue localization of CD138 correlated significantly (p=0.005). PR influenced CD138 tissue distribution, while ER did not. Syndecan-1 localization did not statistically impact RFS. CONCLUSION In DCIS of different nuclear grades, tissue localization of syndecan-1 is significantly divergent, suggesting a specific effect on biology and progression of DCIS.

Often breast cancer can be treated by breast-conserving surgery (BCS), after which 10 % locoregional recurrences (LRR) occur within 10 years. After BCS mastectomy is recommended at first LRR, although another BCS could be possible. Changes in clinical parameters and in tumor biology from primary breast cancer to first and multiple LRR are described and correlated with further LRR and overall survival (OS).

Aberrations of chromosome arm 19p in ovarian cancer were first described decades ago and have been confirmed in recent publications, which have focused on chromosome 11 as a translocation partner. Recently, genetic analysis of the ovarian cancer cell line SKOV3 revealed a rearrangement described as der(19)t(11;19)(q13.2;p13.2), which lead to a fusion protein containing parts of HOOK2 and frame shifted ACTN3 that had unknown functionality. To evaluate the frequency of these breakpoints, we used fluorescence in situ hybridization (FISH) probes flanking these genes for interphase analysis of ovarian cancer cells. We analyzed 49 primary cell cultures of ovarian cancers using FISH probes next to these breakpoints on chromosomes 11 and 19 defined in SKOV3. Co-localizations of the signals in interphase nuclei were considered to be positive fusions when the frequency was over the experimentally calculated cutoff of 24.3% (mean average value for normal ovary cells plus three times the standard deviation). Fusions between 11q13.2 and 19p13.2 were confirmed in 22 (45%) primary cell cultures of ovarian cancers. However, by PCR, the fusion originally described in SKOV3 was not detected in any of the primary cell cultures. Our results confirm other reports and show that these regions are very frequently involved in chromosomal rearrangements in ovarian cancer. Furthermore, they reveal a significant correlation (P = 0.023) of co-localized signals of 11q13.2 and 19p13.2 with low and intermediate grades in ovarian cancer.

Background: Imatinib is a tyrosine kinase inhibitor of BCR-ABL, ABL, PDGFR-α and -β, KIT, and DDR. In solid tumors, it inhibits proliferation and invasiveness and facilitates higher intratumoral cytotoxic drug concentrations. Vinorelbine has good tolerability and efficacy in metastatic breast cancer (MBC). This study evaluates the safety and efficacy of imatinib and vinorelbine in combination. Methods: In a prospective, open-label, phase I/II trial, 400 mg imatinib p.o. daily (corrected from 600 mg) was combined with an escalating dose of vinorelbine i.v. weekly in four dose levels of 10, 15, 20, and 25 mg/m2 (each n ≥ 5) to treat patients with MBC (expressing PDGFR-α and/or -β, and/or KIT). The last patient of each level was treated for >28 days, before enrolment for the next dose level started. Study endpoints were feasibility and tolerability, incidence of hematological and nonhematological toxicity, and clinical efficacy (data cutoff: November 18, 2011). A total of 33 patients have been enrolled, and all dose levels have been fully recruited. One patient is still on study medication. A translational subprotocol is ongoing. Results: All 33 included patients are evaluable for safety (32 within the ITT population). Eleven patients were excluded early from the study (progressive disease, toxicity, and withdrawal of consent). Twenty-two patients participated in the study for >28 days (‘ITT >28'). Within the ITT population, the response rate [complete response (CR) and partial response (PR)] was 9.4% (n = 3), the clinical benefit rate (CBR; CR+PR+stable disease) 50% (n = 16), and the median time to progression (TTP) 155 days. A total of 21.3% of the patients were on study medication for >6 months, and 15.2% for >12 months (mean 140 days, range 15-643). Within ‘ITT >28', the response rate was 13.6%, CBR 72.7%, and median TTP 176 days. The response was independent of the receptor status (PDGFR-α, -β, and KIT). Toxicities were as follows (safety population): 21.6% severe leukopenia, 9.1% severe neutropenia (with 1 febrile neutropenia), 1 case of bowel perforation, 36% diarrhea (3% severe), 84.8% nausea (severe 15.2%), 48.5% vomiting (severe 9.1%), 27.3% infections (severe 6.1%), 12.1% peripheral neuropathy (severe 9.1%), and 36.4% dyspnea (3% severe). Four patients on trial died (nondrug-related). Conclusion: The combination of imatinib and vinorelbine in MBC appeared to be feasible and tolerable. A CBR of 50% (ITT) in pretreated patients suggests that this combination may be active. Although toxicities were frequent, they appeared to be manageable.

Fragestellung: Stromale Fibroblasten sind ein wichtiger Bestandteil des tumor microenvironment und beeinflussen Tumorwachstum und -progression. Stromale Genexpressionssignaturen können die Prognose von Brustkrebspatientinnen sicher vorhersagen. Vorangehend identifizierten wir Gene, welche unterschiedliche Expressionsmuster in cancer associated fibroblasts (CAF) und normalen Fibroblasten zeigten. Ziel dieser Arbeit war die Evaluation der Aldo-keto-reduktasen AKR1C1 und AKR1C2 in stromalen Fibroblasten und Karzinomzellen als prognostische Faktoren beim Mammakarzinom. Beide Kandidatenproteine sind am intratumoralen Progesteronmetabolismus beteiligt und waren in CAF herunterreguliert.