Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
BMC Cancer
Published in: BMC Cancer 1/2018

Open Access 01-12-2018 | Research article

High BCAR1 expression is associated with early PSA recurrence in ERG negative prostate cancer

Authors: Asmus Heumann, Nina Heinemann, Claudia Hube-Magg, Dagmar S. Lang, Katharina Grupp, Martina Kluth, Sarah Minner, Christina Möller-Koop, Markus Graefen, Hans Heinzer, Maria Christina Tsourlakis, Waldemar Wilczak, Corinna Wittmer, Frank Jacobsen, Hartwig Huland, Ronald Simon, Thorsten Schlomm, Guido Sauter, Stefan Steurer, Patrick Lebok, Andrea Hinsch

Published in: BMC Cancer | Issue 1/2018

Login to get access

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.
Appendix
Available only for authorised users
Literature
1.
2.
Camacho Leal Mdel P, Sciortino M, Tornillo G, Colombo S, Defilippi P, Cabodi S. p130Cas/BCAR1 scaffold protein in tissue homeostasis and pathogenesis. Gene. 2015;(1):562, 1–7.
3.
Barrett A, Pellet-Many C, Zachary IC, Evans IM, Frankel P. p130Cas: a key signalling node in health and disease. Cell Signal. 2013;25(4):766–77.CrossRefPubMed
4.
Celhay O, Yacoub M, Irani J, Dore B, Cussenot O, Fromont G. Expression of estrogen related proteins in hormone refractory prostate cancer: association with tumor progression. J Urol. 2010;184(5):2172–8.CrossRefPubMed
5.
Fromont G, Vallancien G, Validire P, Levillain P, Cussenot O. BCAR1 expression in prostate cancer: association with 16q23 LOH status, tumor progression and EGFR/KAI1 staining. Prostate. 2007;67(3):268–73.CrossRefPubMed
6.
Fromont G, Rozet F, Cathelineau X, Ouzzane A, Doucet L, Fournier G, Cussenot O. BCAR1 expression improves prediction of biochemical reccurence after radical prostatectomy. Prostate. 2012;72(12):1359–65.CrossRefPubMed
7.
Erbersdobler A, Fritz H, Schnoger S, Graefen M, Hammerer P, Huland H, Henke RP. Tumour grade, proliferation, apoptosis, microvessel density, p53, and bcl-2 in prostate cancers: differences between tumours located in the transition zone and in the peripheral zone. Eur Urol. 2002;41(1):40–6.CrossRefPubMed
8.
9.
Minner S, Jessen B, Stiedenroth L, Burandt E, Kollermann J, Mirlacher M, Erbersdobler A, Eichelberg C, Fisch M, Brummendorf TH, et al. Low level HER2 overexpression is associated with rapid tumor cell proliferation and poor prognosis in prostate cancer. Clin Cancer Res. 2010;16(5):1553–60.CrossRefPubMed
10.
Minner S, Enodien M, Sirma H, Luebke AM, Krohn A, Mayer PS, Simon R, Tennstedt P, Muller J, Scholz L, et al. ERG status is unrelated to PSA recurrence in radically operated prostate cancer in the absence of antihormonal therapy. Clin Cancer Res. 2011;17(18):5878–88.CrossRefPubMed
11.
Burkhardt L, Fuchs S, Krohn A, Masser S, Mader M, Kluth M, Bachmann F, Huland H, Steuber T, Graefen M, et al. CHD1 is a 5q21 tumor suppressor required for ERG rearrangement in prostate cancer. Cancer Res. 2013;73(9):2795–805.CrossRefPubMed
12.
Kluth M, Hesse J, Heinl A, Krohn A, Steurer S, Sirma H, Simon R, Mayer PS, Schumacher U, Grupp K, et al. Genomic deletion of MAP3K7 at 6q12-22 is associated with early PSA recurrence in prostate cancer and absence of TMPRSS2:ERG fusions. Mod Pathol. 2013;26(7):975–83.CrossRefPubMed
13.
Krohn A, Diedler T, Burkhardt L, Mayer PS, De Silva C, Meyer-Kornblum M, Kotschau D, Tennstedt P, Huang J, Gerhauser C, et al. Genomic deletion of PTEN is associated with tumor progression and early PSA recurrence in ERG fusion-positive and fusion-negative prostate cancer. Am J Pathol. 2012;181(2):401–12.CrossRefPubMed
14.
Krohn A, Seidel A, Burkhardt L, Bachmann F, Mader M, Grupp K, Eichenauer T, Becker A, Adam M, Graefen M, et al. Recurrent deletion of 3p13 targets multiple tumour suppressor genes and defines a distinct subgroup of aggressive ERG fusion-positive prostate cancers. J Pathol. 2013;231(1):130–41.CrossRefPubMed
15.
Taylor BS, Schultz N, Hieronymus H, Gopalan A, Xiao Y, Carver BS, Arora VK, Kaushik P, Cerami E, Reva B, et al. Integrative genomic profiling of human prostate cancer. Cancer Cell. 2010;18(1):11–22.CrossRefPubMedPubMedCentral
16.
Lapointe J, Li C, Giacomini CP, Salari K, Huang S, Wang P, Ferrari M, Hernandez-Boussard T, Brooks JD, Pollack JR. Genomic profiling reveals alternative genetic pathways of prostate tumorigenesis. Cancer Res. 2007;67(18):8504–10.CrossRefPubMed
17.
Weischenfeldt J, Simon R, Feuerbach L, Schlangen K, Weichenhan D, Minner S, Wuttig D, Warnatz HJ, Stehr H, Rausch T, et al. Integrative genomic analyses reveal an androgen-driven somatic alteration landscape in early-onset prostate cancer. Cancer Cell. 2013;23(2):159–70.CrossRefPubMed
18.
Tomlins SA, Rhodes DR, Perner S, Dhanasekaran SM, Mehra R, Sun XW, Varambally S, Cao X, Tchinda J, Kuefer R, et al. Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science. 2005;310(5748):644–8.CrossRefPubMed
19.
Brase JC, Johannes M, Mannsperger H, Falth M, Metzger J, Kacprzyk LA, Andrasiuk T, Gade S, Meister M, Sirma H, et al. TMPRSS2-ERG -specific transcriptional modulation is associated with prostate cancer biomarkers and TGF-beta signaling. BMC Cancer. 2011;11:507.CrossRefPubMedPubMedCentral
20.
Gupta S, Iljin K, Sara H, Mpindi JP, Mirtti T, Vainio P, Rantala J, Alanen K, Nees M, Kallioniemi O. FZD4 as a mediator of ERG oncogene-induced WNT signaling and epithelial-to-mesenchymal transition in human prostate cancer cells. Cancer Res. 2010;70(17):6735–45.CrossRefPubMed
21.
Setlur SR, Mertz KD, Hoshida Y, Demichelis F, Lupien M, Perner S, Sboner A, Pawitan Y, Andren O, Johnson LA, et al. Estrogen-dependent signaling in a molecularly distinct subclass of aggressive prostate cancer. J Natl Cancer Inst. 2008;100(11):815–25.CrossRefPubMedPubMedCentral
22.
Tan SH, Furusato B, Fang X, He F, Mohamed AA, Griner NB, Sood K, Saxena S, Katta S, Young D, et al. Evaluation of ERG responsive proteome in prostate cancer. Prostate. 2014;74(1):70–89.CrossRefPubMed
23.
Jhavar S, Brewer D, Edwards S, Kote-Jarai Z, Attard G, Clark J, Flohr P, Christmas T, Thompson A, Parker M, et al. Integration of ERG gene mapping and gene-expression profiling identifies distinct categories of human prostate cancer. BJU Int. 2009;103(9):1256–69.CrossRefPubMed
24.
Bhattacharya S, Garriga J, Calbo J, Yong T, Haines DS, Grana X. SKP2 associates with p130 and accelerates p130 ubiquitylation and degradation in human cells. Oncogene. 2003;22(16):2443–51.CrossRefPubMed
25.
Tedesco D, Lukas J, Reed SI. The pRb-related protein p130 is regulated by phosphorylation-dependent proteolysis via the protein-ubiquitin ligase SCF (Skp2). Genes Dev. 2002;16(22):2946–57.CrossRefPubMedPubMedCentral
26.
Sengupta S, Henry RW. Regulation of the retinoblastoma-E2F pathway by the ubiquitin-proteasome system. Biochim Biophys Acta. 2015;1849(10):1289–97.CrossRefPubMed
27.
Kim JH, Dhanasekaran SM, Mehra R, Tomlins SA, Gu W, Yu J, Kumar-Sinha C, Cao X, Dash A, Wang L, et al. Integrative analysis of genomic aberrations associated with prostate cancer progression. Cancer Res. 2007;67(17):8229–39.CrossRefPubMed
28.
Bindra RS, Glazer PM. Repression of RAD51 gene expression by E2F4/p130 complexes in hypoxia. Oncogene. 2007;26(14):2048–57.CrossRefPubMed
29.
Kim TM, Ko JH, Hu L, Kim SA, Bishop AJ, Vijg J, Montagna C, Hasty P. RAD51 mutants cause replication defects and chromosomal instability. Mol Cell Biol. 2012;32(18):3663–80.CrossRefPubMedPubMedCentral
30.
Nakamura K, Okamoto A, Katou Y, Yadani C, Shitanda T, Kaweeteerawat C, Takahashi TS, Itoh T, Shirahige K, Masukata H, et al. Rad51 suppresses gross chromosomal rearrangement at centromere in Schizosaccharomyces pombe. EMBO J. 2008;27(22):3036–46.CrossRefPubMedPubMedCentral
31.
Stumm L, Burkhardt L, Steurer S, Simon R, Adam M, Becker A, Sauter G, Minner S, Schlomm T, Sirma H, et al. Strong expression of the neuronal transcription factor FOXP2 is linked to an increased risk of early PSA recurrence in ERG fusion-negative cancers. J Clin Pathol. 2013;66(7):563–8.CrossRefPubMed
32.
Grupp K, Boumesli R, Tsourlakis MC, Koop C, Wilczak W, Adam M, Sauter G, Simon R, Izbicki JR, Graefen M, et al. The prognostic impact of high Nijmegen breakage syndrome (NBS1) gene expression in ERG-negative prostate cancers lacking PTEN deletion is driven by KPNA2 expression. Int J Cancer. 2014;135(6):1399–407.CrossRefPubMed
33.
Grupp K, Jedrzejewska K, Tsourlakis MC, Koop C, Wilczak W, Adam M, Quaas A, Sauter G, Simon R, Izbicki JR, et al. High mitochondria content is associated with prostate cancer disease progression. Mol Cancer. 2013;12(1):145.CrossRefPubMedPubMedCentral
34.
Burdelski C, Bujupi E, Tsourlakis MC, Hube-Magg C, Kluth M, Melling N, Lebok P, Minner S, Koop C, Graefen M, et al. Loss of SOX9 expression is associated with PSA recurrence in ERG-positive and PTEN deleted prostate cancers. PLoS One. 2015;10(6):e0128525.CrossRefPubMedPubMedCentral
35.
Cuzick J, Swanson GP, Fisher G, Brothman AR, Berney DM, Reid JE, Mesher D, Speights VO, Stankiewicz E, Foster CS, et al. Prognostic value of an RNA expression signature derived from cell cycle proliferation genes in patients with prostate cancer: a retrospective study. Lancet Oncol. 2011;12(3):245–55.CrossRefPubMedPubMedCentral
36.
Knezevic D, Goddard AD, Natraj N, Cherbavaz DB, Clark-Langone KM, Snable J, Watson D, Falzarano SM, Magi-Galluzzi C, Klein EA, et al. Analytical validation of the Oncotype DX prostate cancer assay - a clinical RT-PCR assay optimized for prostate needle biopsies. BMC Genomics. 2013;14:690.CrossRefPubMedPubMedCentral
37.
Sauter G, Steurer S, Clauditz TS, Krech T, Wittmer C, Lutz F, Lennartz M, Janssen T, Hakimi N, Simon R, et al. Clinical utility of quantitative Gleason grading in prostate biopsies and prostatectomy specimens. Eur Urol. 2016;69(4):592–8.CrossRefPubMed
Metadata
Title
High BCAR1 expression is associated with early PSA recurrence in ERG negative prostate cancer
Authors
Asmus Heumann
Nina Heinemann
Claudia Hube-Magg
Dagmar S. Lang
Katharina Grupp
Martina Kluth
Sarah Minner
Christina Möller-Koop
Markus Graefen
Hans Heinzer
Maria Christina Tsourlakis
Waldemar Wilczak
Corinna Wittmer
Frank Jacobsen
Hartwig Huland
Ronald Simon
Thorsten Schlomm
Guido Sauter
Stefan Steurer
Patrick Lebok
Andrea Hinsch
Publication date
01-12-2018
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2018
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-017-3956-3

Other articles of this Issue 1/2018

BMC Cancer 1/2018 Go to the issue

Research article

Association between age factors and strategies for promoting participation in gastric and colorectal cancer screenings

Research article

Signaling protein signature predicts clinical outcome of non-small-cell lung cancer

Research article

Could local surgery improve survival in de novo stage IV breast cancer?

Case report

Effective treatment of apatinib in desmoplastic small round cell tumor: a case report and literature review

Study protocol

Korean Society of Coloproctology (KSCP) trial of cONsolidation Chemotherapy for Locally advanced mid or low rectal cancer after neoadjUvant concurrent chemoraDiothErapy: a multicenter, randomized controlled trial (KONCLUDE)

Research article

Temporal and geographic variation in the systemic treatment of advanced prostate cancer
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits