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In breast cancer, the promising efficacy of farnesyltransferase inhibitors (FTIs) in preclinical studies is in contrast to only limited effects in clinical Phase II–III trials. The objective of this study was to explore the clinical relevance of farnesyltransferase β-subunit (FNTB) single nucleotide promoter polymorphisms (FNTB-173 6G > 5G (rs3215788), -609 G > C (rs11623866) and -179 T > A (rs192403314)) in early breast cancer. FNTB genotyping was performed by pyrosequencing in 797 patients from a prospective multicentre observational PiA trial (NCT 01592825). In the total cohort, the FNTB-173 6G > 5G polymorphism was an independent predictor of RFI (HR = 0.568; 95% CI = 0.339–0.949, p = 0.031), OS (HR = 0.629; 95% CI = 0.403–0.980, p = 0.040) and BCSS (HR = 0.433; 95% CI = 0.213–0.882; p = 0.021), whereas the FNTB-609 G > C polymorphism was an independent predictor of RFI (HR = 0.453; 95% CI = 0.226–0.910, p = 0.026) and BCSS (HR = 0.227; 95% CI = 0.075–0.687, p = 0.009). Subtype analysis revealed the independent prognostic relevance of FNTB promoter polymorphisms, particularly in TNBC but not in luminal or HER2-positive intrinsic subtypes. Finally, we used electrophoretic mobility shift assays (EMSAs) to confirm in vitro that the polymorphism FNTB-173 6G > 5G resulted in the differential binding of nuclear proteins from five different breast cancer cell lines. This is the first study on breast cancer suggesting that FNTB promoter polymorphisms (i) are independent prognostic biomarkers, particularly in patients with early TNBC, and (ii) could modulate FNTB’s transcriptional activity.

// Marcus Bauer 1 , Eva Johanna Kantelhardt 2, 3 , Thorsten Stiewe 4, 5, 6 , Andrea Nist 4 , Marco Mernberger 4 , Katharina Politt 4 , Volker Hanf 7 , Tilmann Lantzsch 8 , Christoph Uleer 9 , Susanne Peschel 10 , Jutta John 11 , Jorg Buchmann 12 , Edith Weigert 13 , Karl-Friedrich Burrig 14 , Claudia Wickenhauser 1 , Christoph Thomssen 2 , Frank Bartel 1, * and Martina Vetter 2, * 1 Institute of Pathology, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany 2 Department of Gynaecology, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany 3 Institute of Medical Epidemiology, Biostatistics and Informatics, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany 4 Institute of Molecular Oncology, Universities of Giessen and Marburg Lung Center, German Center for Lung Research (DZL), Marburg, Germany 5 Genomics Core Facility, Philipps-University, Universities of Giessen and Marburg Lung Center, German Center for Lung Research (DZL), Marburg, Germany 6 Universities of Giessen and Marburg Lung Center, German Center for Lung Research (DZL), Marburg, Germany 7 Department of Gynaecology, Hospital Fuerth, Fuerth, Germany 8 Department of Gynaecology, Hospital St. Elisabeth and St. Barbara, Halle (Saale), Germany 9 Onkologische Praxis Uleer, Hildesheim, Germany 10 Department of Gynaecology, St. Bernward Hospital, Hildesheim, Germany 11 Department of Gynaecology, Helios Hospital Hildesheim, Hildesheim, Germany 12 Institute of Pathology, Hospital Martha-Maria, Halle (Saale), Germany 13 Institute of Pathology, Hospital Fuerth, Fuerth, Germany 14 Institute of Pathology Hildesheim, Hildesheim, Germany * Co-senior authors and contributed equally to this work Correspondence to: Frank Bartel, email: frank.bartel@medizin.uni-halle.de Keywords: p53; mutation; tumor suppression; breast cancer; single nucleotide polymorphism Received: September 18, 2018 Accepted: February 15, 2019 Published: March 08, 2019 ABSTRACT Background: Genetic factors play a substantial role in breast cancer etiology. Genes encoding proteins that have key functions in the DNA damage response, such as p53 and its inhibitors MDM2 and MDMX, are most likely candidates to harbor allelic variants that influence breast cancer susceptibility. The aim of our study was to comprehensively analyze the impact of SNPs in the TP53 , MDM2 , and MDMX genes in conjunction with TP53 mutational status regarding the onset and progression of breast cancer. Methods: In specimen from 815 breast cancer patients, five SNPs within the selected genes were analyzed: TP53 – Arg72Pro (rs1042522), MDM2 – SNP285 (rs2279744), SNP309 (rs117039649); MDMX – SNP31826 (rs1563828), and SNP34091 (rs4245739). Classification of the tumors was evaluated by histomorphology. Subtyping according hormone receptor status, HER2-status and proliferation rate enabled provision of the clinico-pathological surrogate of intrinsic subtypes. Results: The homozygous C-allele of MDM2 SNP285 was significantly associated with a younger age-at-diagnosis of 44.2 years, in contrast to G/G- and G/C-patients (62.4, 62.7 yrs., respectively; p = 0.0007; log-Rank-test). In contrast, there was no difference regarding the age-at-diagnosis for patients with the respective genotypes of MDM2 SNP309 ( p = 0.799; log-Rank-test). In patients with estrogen receptor (ER)-positive and TP53 -mutated tumors, however, the T/T-genotype of the MDM2 SNP309 was significantly associated with an earlier average age-at-diagnosis compared with T/G+G/G-patients (53.5 vs. 68.2 yrs; p = 0.002; log-Rank-test). In the triple-negative subgroup, the G/G-patients had an average age-at-diagnosis of 51 years compared with 63 years for SNP309T carriers ( p = 0.004; log-Rank-test) indicating a susceptibility of the G/G genotype for the development of triple negative breast cancer. Patients with the A/A-genotype of MDMX SNP31826 with ER-negative tumors were diagnosed 11 years earlier compared with patients and ER-positive tumors (53.2 vs. 64.4 yrs; p = 0.025, log-Rank-test). Furthermore, in luminal B-like patients (HER2-independent) the C/C-genotype of MDMX SNP34091 was significantly correlated with a decreased event-free survival compared with the A/A-genotype ( p < 0.001; log-Rank-test). Conclusions: We showed that SNPs in the MDM2 and MDMX genes affect at least in part the onset and progression of breast cancer dependent on the ER-status. Our findings provide further evidence for the distinct etiological pathways in ER-negative and ER-positive breast cancers.

Breast cancer is the most common cancer in women worldwide. The tumor microenvironment contributes to tumor progression by inducing cell dissemination from the primary tumor and metastasis. TGFβ signaling is involved in breast cancer progression and is specifically elevated during metastatic transformation in aggressive breast cancer. In this study, we performed genomewide correlation analysis of TGFBR2 expression in a panel of 51 breast cancer cell lines and identified that MET is coregulated with TGFBR2. This correlation was confirmed at the protein level in breast cancer cell lines and human tumor tissues. Flow cytometric analysis of luminal and basal-like breast cancer cell lines and examination of 801 tumor specimens from a prospective cohort of breast cancer patients using reverse phase protein arrays revealed that expression of TGFBR2 and MET is increased in basal-like breast cancer cell lines, as well as in triple-negative breast cancer tumor tissues, compared to other subtypes. Using real-time cell analysis technology, we demonstrated that TGFβ1 triggered hepatocyte growth factor (HGF)-induced and MET-dependent migration in vitro. Bioinformatic analysis predicted that TGFβ1 induces expression of C-ets-1 as a candidate transcription factor regulating MET expression. Indeed, TGFβ1-induced expression of ETS1 and breast cancer cell migration was blocked by knockdown of ETS1. Further, we identified that MET is a direct target of miR-128-3p and that this miRNA is negatively regulated by TGFβ1. Overexpression of miR-128-3p reduced MET expression and abrogated HGF-induced cell migration of invasive breast cancer cells. In conclusion, we have identified that TGFβ1 regulates HGF-induced and MET-mediated cell migration, through positive regulation of C-ets-1 and negative regulation of miR-128-3p expression in basal-like breast cancer cell lines and in triple-negative breast cancer tissue.

Purpose The objective of this study was to compare tumor characteristics, biomarkers, and surrogate subtypes of breast cancer between Sudanese and German women. Methods Tumor characteristics and immunohistochemistry markers (estrogen receptor [ER], progesterone receptor [PR], and human epidermal growth factor receptor 2 [HER2]) were collected from the routine assessment of consecutive patients with invasive breast cancer diagnosed from 2010 to 2015 (Gezira University Pathology Laboratory, Gezira, Sudan) and from 1999 to 2013 (Breast Centre, Martin-Luther-University, Halle, Germany). Results A total of 2,492 patients (German [n = 1,932] and Sudanese [n = 560]) were included. Age at diagnosis ranged from 20 to 94 years. Sudanese women were, on average, 10 years younger than German women, with a mean (± standard deviation) age of 48.8 (13.5) and 58.6 (12.4) years, respectively. The Sudanese women had a higher grade, larger tumor, and more lymph node positivity compared with German women. ER-, PR-, and HER2-negative proportions were 55%, 61.8%, and 71.3%, respectively, for Sudanese women versus 22.7%, 32.3%, and 82.5%, respectively, for German women. The triple-negative subtype was more prevalent in Sudanese women (34.5%) than in German women (14.2%). The strongest factor associated with ER-negative disease was grade III (odds ratio, 19.6; 95% CI 11.6 to 33.4; P < .001). Sudanese patients were at higher risk for ER-negative breast cancer, with an odds ratio of 2.01 ( P = .001; adjusted for age, size, nodal status, histologic type, and grade). Stratified by grade, the influence of origin was observed in grade I and grade II tumors, but not in grade III tumors. Conclusion Sudanese women had more aggressive tumor characteristics and unfavorable prognostic biomarkers. After adjustment, Sudanese origin was still associated with hormone receptor–negative disease, especially in grade I and II tumors. These findings suggest differences in tumor biology among these ethnic groups.

Background In contrast with breast cancers (BCs) in other parts of the world, most previous studies reported that the majority of BCs in sub-Saharan Africa are estrogen-receptor (ER) negative. However, a recent study using the US SEER database showed that the proportion of ER-negative BC is comparable between US-born blacks and West-African born blacks but substantially lower in East African-born blacks, with over 74% of patients Ethiopians or Eritreans. In this paper, we provide the first report on the proportion of ER-negative BC in Ethiopia, and the relation to progesterone-receptor (PgR) status. Methods We analysed 352 female patients with ER results available out of 1208 consecutive female BC patients treated at Addis Ababa-University Hospital, Ethiopia, from June 2005 through December 2010. The influences of age, stage, and histology on the probability of ER-negative tumours were assessed by a log-linear regression model. Results Of the 352 patients, only 35% were ER-negative. The proportion of ER-negative tumours decreased with advancing age at diagnosis and was not affected by histology or stage. For age, the proportion decreased by 6% for each additional 5 years (stage-adjusted prevalence ratio PR = 0.94, 95% CI: 0.89–1.00). About 31% were ER- and PgR-negative, and 69% were ER- and/or PgR-positive. Conclusions Contrary to most previous reports in other parts of sub-Saharan Africa, the majority of patients in Ethiopia are ER-positive rather than ER-negative. These findings are in line with low proportions of ER-negative BCs from East African immigrants within the SEER database, and they have clinical implications for management of BC patients in Ethiopia and other parts of sub-Saharan Africa where ER-status is not ascertained as part of routine management of the disease. Since the majority of patients showed ER-positive BC, Tamoxifen-therapy should be given to all patients even with unknown ER status.

Urokinase-type plasminogen activator (uPA) and its inhibitor plasminogen activator inhibitor-1 (PAI-1) are key factors in tumour invasion and metastasis. Increased levels of uPA and/or PAI-1 in primary tumour tissues correlate with tumour aggressiveness and poor patient outcome [1, 2]. In primary breast cancer, Duffy et al. [3] in 1988 were the first to show that high enzymatic activity of uPA in primary breast cancer tissues was correlated with advanced tumour stage and poor clinical outcome. In 1989, Janicke et al. [4] demonstrated that high uPA antigen levels in primary tumour tissue measured by enzyme-linked immunosorbent assay (ELISA) also predicted poor prognosis. At the same time, it also became apparent that not only antigen levels of uPA but also those of PAI-1 are of prognostic importance in node-negative and node-positive breast cancer patients [4, 5]. Subsequently, many international, mostly European, researchers validated that primary breast cancer patients, and in particular node-negative patients with high tumour tissue antigen content of uPA and/or PAI-1, have a worse probability of disease-free survival (DFS) and overall survival (OS) than patients with low levels of either or both biomarkers [6,7,8,9]. For clinical utility, the combination of uPA/PAI-1 (both low versus either or both high) is superior to either factor taken alone regarding risk group assessment [10]. uPA and PAI-1 render prognostic information independent of established prognostic factors such as tumour size, tumour grade, steroid hormone receptor status, menopausal status [10] and even HER2 status [11,12,13]. Next to their prognostic impact, uPA/PAI-1 also provide predictive information in early breast cancer. Patients with high uPA/PAI-1 have an enhanced benefit from adjuvant chemotherapy compared to those with low levels. Regarding adjuvant endocrine therapy, no such interaction between benefit and uPA/PAI-1 levels could be found [14]. A large meta-analysis conducted by the European Organisation for Research and Treatment of Cancer (EORTC) Receptor and Biomarker Group, comprising 8377 breast cancer patients from 18 independent collectives, validated the prognostic [15] and predictive impact of uPA/PAI-1 [16], thus achieving the highest level of evidence (LOE-I) for clinical utility of a cancer-associated biomarker, according to the American Society of Clinical Oncology (ASCO) tumour marker utility grading system (TMUGS) [17].