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Breast Cancer Research and Treatment
Published in: Breast Cancer Research and Treatment 1/2017

01-02-2017 | Brief Report

Angiopoietin pathway gene expression associated with poor breast cancer survival

Authors: Rajesh Ramanathan, Amy L. Olex, Mikhail Dozmorov, Harry D. Bear, Leopoldo Jose Fernandez, Kazuaki Takabe

Published in: Breast Cancer Research and Treatment | Issue 1/2017

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Abstract

Purpose

Angiogenesis is one of the hallmarks of cancer and is essential for cancer progression and metastasis. However, clinical trials with vascular endothelial growth factor (VEGF) pathway inhibitors have failed to show overall survival benefit in breast cancer. Targeted therapy against the angiopoietin pathway, a downstream angiogenesis cascade, could be effective in breast cancer. This study investigates the association of angiopoietin pathway gene expression with breast cancer survival using a “big data” approach employing RNA sequencing data from The Cancer Genome Atlas (TCGA).

Methods

A total of 888 patients with adequate gene expression, disease-free survival (DFS), and overall survival (OS) data were selected for analysis. DFS and OS were calculated for patients with high and low expression of angiopoietin and VEGF pathway genes using TCGA data. Gene-specific thresholds to dichotomize patients into high and low expression were determined and survival plots were generated.

Results

The TCGA cohort was representative of national breast cancer patients with respect to stage, pathology, and survival. High Ang2 gene expression was associated with not only decreased DFS (p = 0.05), but also decreased OS (p < 0.05). High co-expression of Ang2 and its receptor Tie2 was associated with both decreased DFS and OS (p < 0.05). There was strong correlation between angiopoietin and VEGF pathway genes. While high expression of VEGFA alone was not associated with survival, high co-expression with Ang2 was associated with decreased OS.

Conclusions

This study validates TCGA as a representative database providing genomic data and survival outcomes in breast cancer. Our TCGA data support the angiopoietin pathway as a key mediator in the pathologic angiogenic switch in breast cancer.
Appendix
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Literature
1.
DeSantis CE, Fedewa SA, Goding Sauer A et al (2016) Breast cancer statistics, 2015: convergence of incidence rates between black and white women. CA Cancer J Clin 66:31–42CrossRefPubMed
2.
3.
Pepper MS (2001) Lymphangiogenesis and tumor metastasis: myth or reality? Clin Cancer Res 7:462–468PubMed
4.
Ribatti D, Djonov V (2012) Intussusceptive microvascular growth in tumors. Cancer Lett 316:126–131CrossRefPubMed
5.
Cao Y, Arbiser J, D’Amato RJ et al (2011) Forty-year journey of angiogenesis translational research. Sci Transl Med 3:114rv3PubMed
6.
Augustin HG, Koh GY, Thurston G et al (2009) Control of vascular morphogenesis and homeostasis through the angiopoietin-Tie system. Nat Rev Mol Cell Biol 10:165–177CrossRefPubMed
7.
Thomas M, Augustin HG (2009) The role of the angiopoietins in vascular morphogenesis. Angiogenesis 12:125–137CrossRefPubMed
8.
Gerald D, Chintharlapalli S, Augustin HG et al (2013) Angiopoietin-2: an attractive target for improved antiangiogenic tumor therapy. Cancer Res 73:1649–1657CrossRefPubMed
9.
Scharpfenecker M, Fiedler U, Reiss Y et al (2005) The Tie-2 ligand angiopoietin-2 destabilizes quiescent endothelium through an internal autocrine loop mechanism. J Cell Sci 118:771–780CrossRefPubMed
10.
Keskin D, Kim J, Cooke VG et al (2015) Targeting vascular pericytes in hypoxic tumors increases lung metastasis via angiopoietin-2. Cell Rep 10:1066–1081CrossRefPubMedPubMedCentral
11.
Dieras V, Wildiers H, Jassem J et al (2015) Trebananib (AMG 386) plus weekly paclitaxel with or without bevacizumab as first-line therapy for HER2-negative locally recurrent or metastatic breast cancer: a phase 2 randomized study. Breast 24:182–190CrossRefPubMed
12.
D’Angelo SP, Mahoney MR, Van Tine BA et al (2015) Alliance A091103 a phase II study of the angiopoietin 1 and 2 peptibody trebananib for the treatment of angiosarcoma. Cancer Chemother Pharmacol 75:629–638CrossRefPubMedPubMedCentral
13.
Hong DS, Kurzrock R, Mulay M et al (2014) A phase 1b, open-label study of trebananib plus bevacizumab or motesanib in patients with solid tumours. Oncotarget 5:11154–11167CrossRefPubMedPubMedCentral
14.
Wang SD (2013) Opportunities and challenges of clinical research in the big-data era: from RCT to BCT. J Thorac Dis 5:721–723PubMedPubMedCentral
15.
16.
Ritchie ME, Phipson B, Wu D et al (2015) Limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res 43:e47CrossRefPubMedPubMedCentral
17.
Therneau T (2015) A package for survival analysis in S, v2.38
18.
Howlader N, Noone AM, Krapcho M, Garshell J, Miller D, Altekruse SF, Kosary CL, Yu M, Ruhl J, Tatalovich Z, Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA (eds) (1975–2012) SEER cancer statistics review. National Cancer Institute, Bethesda
19.
Coutelle O, Schiffmann LM, Liwschitz M et al (2015) Dual targeting of angiopoietin-2 and VEGF potentiates effective vascular normalisation without inducing empty basement membrane sleeves in xenograft tumours. Br J Cancer 112:495–503CrossRefPubMedPubMedCentral
20.
21.
Yang XH, Hand RA, Livasy CA et al (2003) Overexpression of the receptor tyrosine kinase Tie-1 intracellular domain in breast cancer. Tumour Biol 24:61–69CrossRefPubMed
22.
Amelio I, Tsvetkov PO, Knight RA et al (2016) SynTarget: an online tool to test the synergetic effect of genes on survival outcome in cancer. Cell Death Differ 23:912CrossRefPubMedPubMedCentral
23.
24.
Curtis C, Shah SP, Chin SF et al (2012) The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups. Nature 486:346–352PubMedPubMedCentral
25.
Hatzis C, Pusztai L, Valero V et al (2011) A genomic predictor of response and survival following taxane–anthracycline chemotherapy for invasive breast cancer. J Am Med Assoc 305:1873–1881CrossRef
26.
Itoh M, Iwamoto T, Matsuoka J et al (2014) Estrogen receptor (ER) mRNA expression and molecular subtype distribution in ER-negative/progesterone receptor-positive breast cancers. Breast Cancer Res Treat 143:403–409CrossRefPubMed
27.
Miller K, Wang M, Gralow J et al (2007) Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med 357:2666–2676CrossRefPubMed
28.
Pivot X, Schneeweiss A, Verma S et al (2011) Efficacy and safety of bevacizumab in combination with docetaxel for the first-line treatment of elderly patients with locally recurrent or metastatic breast cancer: results from AVADO. Eur J Cancer 47:2387–2395CrossRefPubMed
29.
Smith IE, Pierga JY, Biganzoli L et al (2011) First-line bevacizumab plus taxane-based chemotherapy for locally recurrent or metastatic breast cancer: safety and efficacy in an open-label study in 2,251 patients. Ann Oncol 22:595–602CrossRefPubMed
30.
von Minckwitz G, Puglisi F, Cortes J et al (2014) Bevacizumab plus chemotherapy versus chemotherapy alone as second-line treatment for patients with HER2-negative locally recurrent or metastatic breast cancer after first-line treatment with bevacizumab plus chemotherapy (TANIA): an open-label, randomised phase 3 trial. Lancet Oncol 15:1269–1278CrossRef
31.
Gligorov J, Doval D, Bines J et al (2014) Maintenance capecitabine and bevacizumab versus bevacizumab alone after initial first-line bevacizumab and docetaxel for patients with HER2-negative metastatic breast cancer (IMELDA): a randomised, open-label, phase 3 trial. Lancet Oncol 15:1351–1360CrossRefPubMed
32.
Gianni L, Romieu GH, Lichinitser M et al (2013) AVEREL: a randomized phase III Trial evaluating bevacizumab in combination with docetaxel and trastuzumab as first-line therapy for HER2-positive locally recurrent/metastatic breast cancer. J Clin Oncol 31:1719–1725CrossRefPubMed
33.
34.
Miller KD, Chap LI, Holmes FA et al (2005) Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol 23:792–799CrossRefPubMed
35.
von Minckwitz G, Eidtmann H, Rezai M et al (2012) Neoadjuvant chemotherapy and bevacizumab for HER2-negative breast cancer. N Engl J Med 366:299–309CrossRef
36.
37.
Børresen-Dale AL (2016) Molecular Evolution Under Neoadjuvant Chemotherapy. In: Proceedings of the thirty-eighth annual CTRC-AACR San Antonio breast cancer symposium: 2015 Dec 8–12, San Antonio, TX. AACR, Philadelphia
38.
39.
Etoh T, Inoue H, Tanaka S et al (2001) Angiopoietin-2 is related to tumor angiogenesis in gastric carcinoma: possible in vivo regulation via induction of proteases. Cancer Res 61:2145–2153PubMed
40.
Hu B, Guo P, Fang Q et al (2003) Angiopoietin-2 induces human glioma invasion through the activation of matrix metalloprotease-2. Proc Natl Acad Sci USA 100:8904–8909CrossRefPubMedPubMedCentral
41.
Oliner J, Min H, Leal J et al (2004) Suppression of angiogenesis and tumor growth by selective inhibition of angiopoietin-2. Cancer Cell 6:507–516CrossRefPubMed
42.
Imanishi Y, Hu B, Jarzynka MJ et al (2007) Angiopoietin-2 stimulates breast cancer metastasis through the alpha(5)beta(1) integrin-mediated pathway. Cancer Res 67:4254–4263CrossRefPubMedPubMedCentral
43.
Zhou YZ, Fang XQ, Li H et al (2007) Role of serum angiopoietin-2 level in screening for esophageal squamous cell cancer and its precursors. Chin Med J (Engl) 120:1216–1219
44.
Kuboki S, Shimizu H, Mitsuhashi N et al (2008) Angiopoietin-2 levels in the hepatic vein as a useful predictor of tumor invasiveness and prognosis in human hepatocellular carcinoma. J Gastroenterol Hepatol 23:e157–e164CrossRefPubMed
45.
Helfrich I, Edler L, Sucker A et al (2009) Angiopoietin-2 levels are associated with disease progression in metastatic malignant melanoma. Clin Cancer Res 15:1384–1392CrossRefPubMed
46.
Park JH, Park KJ, Kim YS et al (2007) Serum angiopoietin-2 as a clinical marker for lung cancer. Chest 132:200–206CrossRefPubMed
47.
Takanami I (2004) Overexpression of Ang-2 mRNA in non-small cell lung cancer: association with angiogenesis and poor prognosis. Oncol Rep 12:849–853PubMed
48.
Srivastava K, Hu J, Korn C et al (2014) Postsurgical adjuvant tumor therapy by combining anti-angiopoietin-2 and metronomic chemotherapy limits metastatic growth. Cancer Cell 26:880–895CrossRefPubMed
49.
Herbst RS, Hong D, Chap L et al (2009) Safety, pharmacokinetics, and antitumor activity of AMG 386, a selective angiopoietin inhibitor, in adult patients with advanced solid tumors. J Clin Oncol 27:3557–3565CrossRefPubMed
50.
51.
Nagahashi M, Ramachandran S, Kim EY et al (2012) Sphingosine-1-phosphate produced by sphingosine kinase 1 promotes breast cancer progression by stimulating angiogenesis and lymphangiogenesis. Cancer Res 72:726–735CrossRefPubMedPubMedCentral
Metadata
Title
Angiopoietin pathway gene expression associated with poor breast cancer survival
Authors
Rajesh Ramanathan
Amy L. Olex
Mikhail Dozmorov
Harry D. Bear
Leopoldo Jose Fernandez
Kazuaki Takabe
Publication date
01-02-2017
Publisher
Springer US
Published in
Breast Cancer Research and Treatment / Issue 1/2017
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI
https://doi.org/10.1007/s10549-017-4102-2

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