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High BCAR1 Expression Is Associated with Early PSA Recurrence in ERG Negative Prostate Cancer Asmus Heumann1†, Nina Heinemann1†, Claudia Hube-Magg1, Dagmar S

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High BCAR1 Expression Is Associated with Early PSA Recurrence in ERG Negative Prostate Cancer Asmus Heumann1†, Nina Heinemann1†, Claudia Hube-Magg1, Dagmar S Heumann et al. BMC Cancer (2018) 18:37 DOI 10.1186/s12885-017-3956-3 RESEARCHARTICLE Open Access High BCAR1 expression is associated with early PSA recurrence in ERG negative prostate cancer Asmus Heumann1†, Nina Heinemann1†, Claudia Hube-Magg1, Dagmar S. Lang1, Katharina Grupp2, Martina Kluth1, Sarah Minner1, Christina Möller-Koop1,MarkusGraefen3, Hans Heinzer3, Maria Christina Tsourlakis1, Waldemar Wilczak1, Corinna Wittmer1,FrankJacobsen1,HartwigHuland3, Ronald Simon1* ,ThorstenSchlomm3,4, Guido Sauter1, Stefan Steurer1,PatrickLebok1 and Andrea Hinsch1 Abstract Background: Breast cancer anti-estrogen resistance 1 (BCAR1/p130cas) is a hub for diverse oncogenic signaling cascades and promotes tumor development and progression. Methods: To understand the effect of BCAR1 in prostate cancer, we analyzed its expression on more than 11,000 prostate cancer samples. BCAR1 expression levels were compared with clinical characteristics, PSA recurrence, molecular subtype defined by ERG status and 3p, 5q, 6q and PTEN deletion. Results: BCAR1 staining was barely detectable in normal prostate glands but seen in 77.6% of 9472 interpretable cancers, including strong expression in 38.5%, moderate in 23.2% and weak in 15.9% of cases. BCAR1 up regulation was associated with positive ERG status (p < 0.0001), high Gleason score (p < 0.0001), advanced pathological tumor stage (p = 0.0082), lower preoperative PSA level (p < 0.0001), increased cell proliferation (p < 0.0001), early PSA recurrence (p = 0.0008), and predicted prognosis independently from clinico-pathological parameters available at the time of the initial biopsy. However, subset analyses revealed that the prognostic impact of BCAR1 expression was limited to ERG-negative cancer. That BCAR1 up regulation was linked to almost all analyzed deletions (p < 0.0001 each for PTEN, 5q, 6q deletion) may suggest a functional link to genomic instability. Conclusion: The results of our study identify BCAR1 as a prognostic biomarker with potential clinical value for risk stratification of ERG-negative prostate cancer. Keywords: BCAR1, Prostate cancer, Tissue microarray, Prognosis, Immunohistochemistry Background powerful but not sufficient for optimal individual treat- Prostate cancer is the most common cancer in men in ment choice. It is therefore hoped that the analysis of Western societies [1]. At diagnosis the majority of pros- further biomarkers may lead to improved individual pre- tate cancer is curable, but a minor subset of tumors is diction of tumor aggressiveness in the future. characterized by aggressive growth and metastasis. Des- Breast cancer anti-estrogen resistance 1 (BCAR1/ pite recent advance in research for biomarkers, the p130Cas) is a scaffold protein that serves as a hub in cel- established pre-treatment prognostic parameters are lular signaling. It facilitates the assembly of multi- Gleason score, tumor extent on biopsy, pre-operative protein complexes regulating diverse cellular processes PSA and clinical parameters. These data are statistically such as migration, invasion, proliferation and survival. BCAR1 participates in signal conduction of major onco- * Correspondence: [email protected] genic kinases such as Abl, FAK and Src. Consequently, †Equal contributors BCAR1 has been shown to be overexpressed in diverse 1Institute of Pathology, University Medical Center Hamburg-Eppendorf, malignancies, including cancers of the breast, lung, liver Martinistr. 52, 20246 Hamburg, Germany Full list of author information is available at the end of the article and brain, and has been linked to adverse features in © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Heumann et al. BMC Cancer (2018) 18:37 Page 2 of 10 Fig. 1 Representative image of BCAR1 expression (a) negative, (b) weak, (c) moderate, (d) strong staining at 100×, and 400× (inset) magnification these entities (reviewed in [2, 3]). Initial evidence also large cohort of prostate cancer patients. For this pur- suggests a role for BCAR1 in prostate cancer progres- pose, we chose our tissue microarray (TMA) comprising sion, as its overexpression was linked to an unfavor- >11,000 prostate cancer specimens with attached clinical able tumor phenotype and biochemical relapse in and molecular data. Our study highlight that BCAR1 ex- three studies analyzing 110 [4], 130 [5] and 242 [6] pression is associated with unfavorable tumor features prostate cancer specimens. and that the prognostic impact of BCAR1 is limited to Based on these data, we intended to confirm the bio- ERG-negative cancers. logic and prognostic role of BCAR1 protein in a very Methods Patients Radical prostatectomy samples were taken from 11,152 patients, undergoing surgery between 1992 and 2011 at the Department of Urology and the Martini Clinics at the University Medical Center Hamburg-Eppendorf. Follow-up was available from 9695 patients (median 36.8 months; range 1 to 228 months; Additional file 1: Table S1). Prostate specific antigen (PSA) recurrence was defined as a postoperative PSA of ≥0,2 ng/ml. Histo- logical analysis of prostate specimen was done as de- tailed in [7] and TMA were produced as described earlier in [8]. Each TMA block contained various control tissues, including normal prostate tissue. The molecular database attached to this TMA contained results on Ki67 expression in 7010 (expanded from [9]), ERG ex- pression in 9628, ERG break apart fluorescence in-situ hybridization (FISH) analysis in 6106 (expanded from [10]), and deletion status of 5q21 in 3037 (expanded Fig. 2 Association between BCAR1 staining and ERG-status from [11]), 6q15 in 3528 (expanded from [12]), PTEN in Heumann et al. BMC Cancer (2018) 18:37 Page 3 of 10 Table 1 Association between BCAR1 staining and prostate cancer clinical characteristics Parameter BCAR1 (%) N evaluable Negative Weak Moderate Strong P value All cancers 9472 22.4 15.9 23.2 38.5 Tumor stage pT2 6170 23.7 15.9 23.1 37.4 0.0082 pT3a 2138 20.4 16.1 24.2 39.3 pT3b-pT4 1160 19.5 15.6 21.7 43.2 Gleason score ≤ 3 + 3 2186 27.2 19.0 23.1 30.8 < 0.0001 3 + 4 5133 21.9 14.9 23.5 39.8 3 + 4 Tertiary 5 345 22.9 14.5 23.8 38.8 4 + 3 893 18.4 17.6 21.7 42.3 4 + 3 Tertiary 5 464 15.1 14.4 22.4 48.1 ≥ 4 + 4 445 20.9 11.7 23.2 44.3 Lymph node metastasis N0 5262 20.9 16.1 23.2 40.0 <0.0001 N+ 494 21.3 12.8 21.5 44.5 Preoperative PSA level (ng/ml) < 4 1480 16.9 15.0 24.0 44.1 <0.0001 4–10 5475 21.6 15.9 23.5 39.0 10–20 1817 26.0 15.9 22.5 35.6 > 20 638 32.1 17.6 19.0 31.4 Surgical margin Negative 7566 22.1 15.8 23.3 38.8 <0.0001 Positive 1794 23.4 16.2 22.9 37.6 6130 (expanded from [13]), and 3p13 in 1290 (expanded survival curves were calculated and the Log-Rank test was from [14]) tumors. applied to detect differences. Cox proportional hazards regression was performed to look for statistical independ- Immunohistochemistry ence of pathological, molecular and clinical variables. Sep- Freshly cut TMA sections were stained on 1 day and arate analyses were done using various sets of parameters in one experiment. Slides were deparaffinized and ex- available either before or after prostatectomy. posed to heat-induced antigen retrieval at 121 °C in Tris-EDTA-citrate buffer (pH 7.8). BCAR1 specific Results mouse monoclonal antibody (clone M144, Abcam, Technical issues Cambridge, UK) was applied at 1/37.5 dilution at 37 ° Eighty four point nine percent of the 11,152 arrayed C for 60 min. BCAR1 staining was visualized with the tumor samples were interpretable in our TMA analysis. EnVision Kit (Dako, Glostrup, Denmark) according to 15.1% were non-informative, which included 1679 spots the manufacturer’s directions. Staining was localized with lack of tissue samples or absence of unequivocal to the cytoplasm. It was homogenous in the analyzed cancer tissue in the TMA spot. tissue samples and therefore staining intensity was semi quantitatively assessed as negative, weak, moder- ate, and strong. BCAR1 expression BCAR1 staining was generally absent or very faint in Statistics normal prostatic secretory cells, basal cells and stromal JPM 9 software (SAS Institute Inc., NC, USA) was used. cells. In cancer cells, cytoplasmic BCAR1 expression was Contingency tables and the likelihood-ratio chi2-test were observed in 77.6% of 9472 interpretable prostate cancers; performed to find associations between molecular param- weak in 15.9%, moderate in 23.2%, and strong in 38.5% eters and clinical tumor characteristics. Kaplan-Meier of cases. Fig. 1 shows representative images. BCAR1 Heumann et al. BMC Cancer (2018) 18:37 Page 4 of 10 Table 2 Association between BCAR1 expression and Ki67-labeling rearrangements and ERG expression in prostate can- index in different Gleason scores cers (p < 0.0001 each; Fig. 2). For example, moderate Gleason score BCAR1 expression Ki67- labeling index P value or strong BCAR1 staining was observed in 79.3% of N Mean ± SD cancers with ERG rearrangement detected by FISH All Negative 1422 1.6 0.07 <0.0001 but found in only 57.3% of cancers without such Weak 1063 2.5 0.08 rearrangements (p < 0.0001).
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