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
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Clinical & Experimental Metastasis
Published in: Clinical & Experimental Metastasis 4/2016

Open Access 01-04-2016 | Research Paper

β-catenin-independent WNT signaling and Ki67 in contrast to the estrogen receptor status are prognostic and associated with poor prognosis in breast cancer liver metastases

Authors: Annalen Bleckmann, Lena-Christin Conradi, Kerstin Menck, Nadine Annette Schmick, Antonia Schubert, Eva Rietkötter, Jetcy Arackal, Peter Middel, Alexandra Schambony, Torsten Liersch, Kia Homayounfar, Tim Beißbarth, Florian Klemm, Claudia Binder, Tobias Pukrop

Published in: Clinical & Experimental Metastasis | Issue 4/2016

Login to get access

Abstract

Liver metastasis development in breast cancer patients is common and confers a poor prognosis. So far, the prognostic significance of surgical resection and clinical relevance of biomarker analysis in metastatic tissue have barely been investigated. We previously demonstrated an impact of WNT signaling in breast cancer brain metastasis. This study aimed to investigate the value of established prognostic markers and WNT signaling components in liver metastases. Overall N = 34 breast cancer liver metastases (with matched primaries in 19/34 cases) were included in this retrospective study. Primaries and metastatic samples were analyzed for their expression of the estrogen (ER) and progesterone receptor, HER-2, Ki67, and various WNT signaling-components by immunohistochemistry. Furthermore, β-catenin-dependent and -independent WNT scores were generated and analyzed for their prognostic value. Additionally, the influence of the alternative WNT receptor ROR on signaling and invasiveness was analyzed in vitro. ER positivity (HR 0.09, 95 % CI 0.01–0.56) and high Ki67 (HR 3.68, 95 % CI 1.12–12.06) in the primaries had prognostic impact. However, only Ki67 remained prognostic in the metastatic tissue (HR 2.46, 95 % CI 1.11–5.44). Additionally, the β-catenin-independent WNT score correlated with reduced overall survival only in the metastasized situation (HR 2.19, 95 % CI 1.02–4.69, p = 0.0391). This is in line with the in vitro results of the alternative WNT receptors ROR1 and ROR2, which foster invasion. In breast cancer, the value of prognostic markers established in primary tumors cannot directly be translated to metastases. Our results revealed β-catenin-independent WNT signaling to be associated with poor prognosis in patients with breast cancer liver metastasis.
Appendix
Available only for authorised users
Literature
1.
De Angelis R et al (2014) Cancer survival in Europe 1999–2007 by country and age: results of EUROCARE–5-a population-based study. Lancet Oncol 15(1):23–34CrossRefPubMed
2.
Cardoso F et al. (2014) ESO-ESMO 2nd international consensus guidelines for advanced breast cancer (ABC2) dagger. Annals of oncology: Official Journal of the European Society for Medical Oncology/ESMO vol 25(10), pp 1871–88
3.
Ruiterkamp J, Ernst MF (2011) The role of surgery in metastatic breast cancer. Eur J Cancer 47(Suppl 3):S6–S22CrossRefPubMed
4.
Choti MA (2014) Liver-directed treatments for metastatic colorectal cancer. Curr Treat Options Oncol 15(3):456–464CrossRefPubMed
5.
Elsberger B, Roxburgh CS, Horgan PG (2014) Is there a role for surgical resections of hepatic breast cancer metastases? Hepatogastroenterology 61(129):181–186PubMed
6.
Page AJ et al (2014) Advances in understanding of colorectal liver metastasis and implications for the clinic. Expert Rev Gastroenterol Hepatol 9(2):245–259 CrossRefPubMed
7.
Krop IE et al (2012) A phase II study of trastuzumab emtansine in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer who were previously treated with trastuzumab, lapatinib, an anthracycline, a taxane, and capecitabine. J Clin Oncol 30(26):3234–3241CrossRefPubMed
8.
Emons G, Ghadimi M, Grade M (2015) General principles of tumour biology in visceral surgery. Zentralbl Chir 140(1):74–82PubMed
9.
Nguyen DX, Bos PD, Massague J (2009) Metastasis: from dissemination to organ-specific colonization. Nat Rev Cancer 9(4):274–284CrossRefPubMed
10.
11.
Nguyen DX, Massague J (2007) Genetic determinants of cancer metastasis. Nat Rev Genet 8(5):341–352CrossRefPubMed
12.
Langley RR, Fidler IJ (2011) The seed and soil hypothesis revisited—the role of tumor-stroma interactions in metastasis to different organs. Int J Cancer (J Int Cancer), vol 128(11), pp 2527–2535
13.
Gerlinger M et al (2012) Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med 366(10):883–892CrossRefPubMed
14.
Huang Y et al (2014) Multilayered molecular profiling supported the monoclonal origin of metastatic renal cell carcinoma. Int J Cancer (J Int Cancer), vol 135(1), pp 78–87
15.
Klein CA (2009) Parallel progression of primary tumours and metastases. Nat Rev Cancer 9(4):302–312CrossRefPubMed
16.
Stoecklein NH, Klein CA (2010) Genetic disparity between primary tumours, disseminated tumour cells, and manifest metastasis. Int J Cancer (J Int Cancer), vol 126(3), pp 589–98
17.
Chambers AF, Groom AC, Macdonald IC (2002) Dissemination and growth of cancer cells in metastatic sites. Nat Rev Cancer 2(8):563–572CrossRefPubMed
18.
19.
Kienast Y et al (2009) Real-time imaging reveals the single steps of brain metastasis formation. Nat Med 16(1):116–122CrossRefPubMed
20.
21.
Pukrop T et al (2010) Microglia promote colonization of brain tissue by breast cancer cells in a Wnt-dependent way. Glia 58(12):1477–1489PubMed
22.
Bleckmann A et al (2013) Nuclear LEF1/TCF4 correlate with poor prognosis but not with nuclear beta-catenin in cerebral metastasis of lung adenocarcinomas. Clin Exp Metastasis 30(4):471–482CrossRefPubMedPubMedCentral
23.
Klemm F et al (2011) beta-catenin-independent WNT signaling in basal-like breast cancer and brain metastasis. Carcinogenesis 32(3):434–442CrossRefPubMed
24.
Clevers H, Loh KM, Nusse R (2014) Stem cell signaling. An integral program for tissue renewal and regeneration: wnt signaling and stem cell control. Science 346(6205):1248012CrossRefPubMed
25.
26.
27.
Gessert S, Kuhl M (2010) The multiple phases and faces of wnt signaling during cardiac differentiation and development. Circ Res 107(2):186–199CrossRefPubMed
28.
Ocana OH et al (2012) Metastatic colonization requires the repression of the epithelial-mesenchymal transition inducer Prrx1. Cancer Cell 22(6):709–724CrossRefPubMed
29.
30.
Li J, Zhou BP (2011) Activation of beta-catenin and Akt pathways by Twist are critical for the maintenance of EMT associated cancer stem cell-like characters. BMC Cancer 11:49CrossRefPubMedPubMedCentral
31.
van de Wetering M et al (2001) Mutant E-cadherin breast cancer cells do not display constitutive Wnt signaling. Cancer Res 61(1):278–284PubMed
32.
Gilles C et al (2003) Transactivation of vimentin by beta-catenin in human breast cancer cells. Cancer Res 63(10):2658–2664PubMed
33.
34.
Henry C et al (2015) Expression of the novel Wnt receptor ROR2 is increased in breast cancer and may regulate both beta-catenin dependent and independent Wnt signalling. J Cancer Res Clin Oncol 141(2):243–254CrossRefPubMed
35.
Kikuchi A et al (2012) Wnt5a: its signalling, functions and implication in diseases. Acta Physiol 204(1):17–33CrossRef
36.
Pukrop T, Binder C (2008) The complex pathways of Wnt 5a in cancer progression. J Mol Med 86(3):259–266CrossRefPubMed
37.
Witte F et al (2010) Receptor tyrosine kinase-like orphan receptor 2 (ROR2) and Indian hedgehog regulate digit outgrowth mediated by the phalanx-forming region. Proc Natl Acad Sci USA 107(32):14211–14216CrossRefPubMedPubMedCentral
38.
Gentzel M et al (2015) Distinct functionality of dishevelled isoforms on Ca2 +/calmodulin-dependent protein kinase 2 (CamKII) in Xenopus gastrulation. Mol Biol Cell 26(5):966–977CrossRefPubMedPubMedCentral
39.
Hagemann T et al (2004) Enhanced invasiveness of breast cancer cell lines upon co-cultivation with macrophages is due to TNF-alpha dependent up-regulation of matrix metalloproteases. Carcinogenesis 25(8):1543–1549CrossRefPubMed
40.
van de Vijver M et al (2007) Chromogenic in situ hybridisation for the assessment of HER2 status in breast cancer: an international validation ring study. Breast Cancer Res 9(5):R68CrossRefPubMedPubMedCentral
41.
McShane LM et al (2006) REporting recommendations for tumor MARKer prognostic studies (REMARK). Breast Cancer Res Treat 100(2):229–235CrossRefPubMed
42.
Nishita M et al (2010) Ror2/Frizzled complex mediates Wnt5a-induced AP-1 activation by regulating Dishevelled polymerization. Mol Cell Biol 30(14):3610–3619CrossRefPubMedPubMedCentral
43.
Gao S et al (2014) Dsh homolog DVL3 mediates resistance to IGFIR inhibition by regulating IGF-RAS signaling. Cancer Res 74(20):5866–5877CrossRefPubMed
44.
Hegazy SA et al (2013) Disheveled proteins promote cell growth and tumorigenicity in ALK-positive anaplastic large cell lymphoma. Cell Signal 25(1):295–307CrossRefPubMed
45.
Kwan HT et al (2013) AMPK activators suppress cervical cancer cell growth through inhibition of DVL3 mediated Wnt/beta-catenin signaling activity. PLoS ONE 8(1):e53597CrossRefPubMedPubMedCentral
46.
Zhao Y et al (2010) Dishevelled-1 and dishevelled-3 affect cell invasion mainly through canonical and noncanonical Wnt pathway, respectively, and associate with poor prognosis in nonsmall cell lung cancer. Mol Carcinog 49(8):760–770PubMed
47.
48.
Sabol M et al (2014) Surgical management of breast cancer liver metastases. Neoplasma 61(5):601–606CrossRefPubMed
49.
Van Cutsem E et al (2014) Metastatic colorectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 25(Suppl 3):1–9CrossRef
50.
51.
Klemm F, Joyce JA (2014) Microenvironmental regulation of therapeutic response in cancer. Trends Cell Biol 25(4):198–213CrossRefPubMed
52.
Devaud C et al (2014) Tissues in different anatomical sites can sculpt and vary the tumor microenvironment to affect responses to therapy. Mol Ther 22(1):18–27CrossRefPubMedPubMedCentral
53.
Shah SP et al (2009) Mutational evolution in a lobular breast tumour profiled at single nucleotide resolution. Nature 461(7265):809–813CrossRefPubMed
54.
55.
Kroigard AB et al (2015) Clonal expansion and linear genome evolution through breast cancer progression from pre-invasive stages to asynchronous metastasis. Oncotarget 6(8):5634–5649CrossRefPubMedPubMedCentral
56.
Brastianos PK, Cahill DP (2015) Management of brain metastases in the era of targeted and immunomodulatory therapies. Oncology 29(4):261–263PubMed
57.
Saunus JM et al (2015) Integrated genomic and transcriptomic analysis of human brain metastases identifies alterations of potential clinical significance. J Pathol 237(3):363–378CrossRefPubMed
58.
Luga V et al (2012) Exosomes mediate stromal mobilization of autocrine Wnt-PCP signaling in breast cancer cell migration. Cell 151(7):1542–1556CrossRefPubMed
59.
Pukrop T et al (2006) Wnt 5a signaling is critical for macrophage-induced invasion of breast cancer cell lines. Proc Natl Acad Sci USA 103(14):5454–5459CrossRefPubMedPubMedCentral
60.
Brastianos PK et al (2015) Genomic characterization of brain metastases reveals branched evolution and potential therapeutic targets. Cancer Discov 5(11):1164–1177CrossRefPubMed
61.
Paik PK et al (2015) Next-generation sequencing of stage IV squamous cell lung cancers reveals an association of PI3 K aberrations and evidence of clonal heterogeneity in patients with brain metastases. Cancer Discov 5(6):610–621CrossRefPubMedPubMedCentral
Metadata
Title
β-catenin-independent WNT signaling and Ki67 in contrast to the estrogen receptor status are prognostic and associated with poor prognosis in breast cancer liver metastases
Authors
Annalen Bleckmann
Lena-Christin Conradi
Kerstin Menck
Nadine Annette Schmick
Antonia Schubert
Eva Rietkötter
Jetcy Arackal
Peter Middel
Alexandra Schambony
Torsten Liersch
Kia Homayounfar
Tim Beißbarth
Florian Klemm
Claudia Binder
Tobias Pukrop
Publication date
01-04-2016
Publisher
Springer Netherlands
Published in
Clinical & Experimental Metastasis / Issue 4/2016
Print ISSN: 0262-0898
Electronic ISSN: 1573-7276
DOI
https://doi.org/10.1007/s10585-016-9780-3

Other articles of this Issue 4/2016

Clinical & Experimental Metastasis 4/2016 Go to the issue

Research Paper

Metformin may protect nondiabetic breast cancer women from metastasis

Research Paper

Characterization of passive permeability at the blood–tumor barrier in five preclinical models of brain metastases of breast cancer

Research Paper

Spheroid culture of LuCaP 136 patient-derived xenograft enables versatile preclinical models of prostate cancer

Research Paper

Versican and vascular endothelial growth factor expression levels in peritoneal metastases from colorectal cancer are associated with survival after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy

Research Paper

MiR-193a-3p and miR-193a-5p suppress the metastasis of human osteosarcoma cells by down-regulating Rab27B and SRR, respectively

Research Paper

Repositioning “old” drugs for new causes: identifying new inhibitors of prostate cancer cell migration and invasion
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