Top

Published in:

01-07-2009 | Preclinical Study

Effects of infiltrating lymphocytes and estrogen receptor on gene expression and prognosis in breast cancer

Authors: Alberto Calabrò, Tim Beissbarth, Ruprecht Kuner, Michael Stojanov, Axel Benner, Martin Asslaber, Ferdinand Ploner, Kurt Zatloukal, Hellmut Samonigg, Annemarie Poustka, Holger Sültmann

Published in: Breast Cancer Research and Treatment | Issue 1/2009

Abstract

The involvement of the immune system for the course of breast cancer, as evidenced by varying degrees of lymphocyte infiltration (LI) into the tumor is still poorly understood. The aim of this study was to evaluate the prognostic value of LI in breast cancer samples using microarray-based screening for LI-associated genes. Starting from the observation that most published ER gene signatures are heavily influenced by the LI effect, we developed and applied a novel approach to dissect molecular signatures. Further, a meta-analysis encompassing 1,044 hybridizations showed that LI alone is not sufficient to highlight breast cancer patients with different prognosis. However, for ER positive patients, high LI was associated with shorter survival times, whereas for ER negative patients, high LI is significantly associated with longer survival. Annotation of LI, in addition to ER status, is important for breast cancer patient prognosis and may have implications for the future treatment of breast cancer.

Available only for authorised users

The R core project team (2007) R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria

Aaltomaa S, Lipponen P, Eskelinen M, Kosma VM, Marin S, Alhava E et al (1992) Lymphocyte infiltrates as a prognostic variable in female breast cancer. Eur J Cancer 28A:859–864. doi:10.1016/0959-8049(92)90134-N PubMedCrossRef

Alexe G, Dalgin GS, Scanfeld D, Tamayo P, Mesirov JP, DeLisi C et al (2007) High expression of lymphocyte-associated genes in node-negative HER2+ breast cancers correlates with lower recurrence rates. Cancer Res 67:10669–10676. doi:10.1158/0008-5472.CAN-07-0539 PubMedCrossRef

Aspord C, Pedroza-Gonzalez A, Gallegos M, Tindle S, Burton EC, Su D et al (2007) Breast cancer instructs dendritic cells to prime interleukin 13-secreting CD4+ T cells that facilitate tumor development. J Exp Med 204:1037–1047. doi:10.1084/jem.20061120 PubMedCrossRef

Asslaber M, Zatloukal K (2007) Biobanks: transnational, European and global networks. Brief Funct Genomic Proteomic 6:193–201PubMedCrossRef

Balkwill F, Mantovani A (2001) Inflammation and cancer: back to Virchow? Lancet 357:539–545. doi:10.1016/S0140-6736(00)04046-0 PubMedCrossRef

Bates GJ, Fox SB, Han C, Leek RD, Garcia JF, Harris AL et al (2006) Quantification of regulatory T cells enables the identification of high-risk breast cancer patients and those at risk of late relapse. J Clin Oncol 24:5373–5380. doi:10.1200/JCO.2006.05.9584 PubMedCrossRef

Beissbarth T, Speed TP (2004) GOstat: find statistically overrepresented Gene Ontologies within a group of genes. Bioinformatics 20:1464–1465. doi:10.1093/bioinformatics/bth088 PubMedCrossRef

Bertucci F, Finetti P, Cervera N, Charafe-Jauffret E, Mamessier E, Adelaide J et al (2006) Gene expression profiling shows medullary breast cancer is a subgroup of basal breast cancers. Cancer Res 66:4636–4644. doi:10.1158/0008-5472.CAN-06-0031 PubMedCrossRef

10.

Bild AH, Yao G, Chang JT, Wang Q, Potti A, Chasse D et al (2006) Oncogenic pathway signatures in human cancers as a guide to targeted therapies. Nature 439:353–357. doi:10.1038/nature04296 PubMedCrossRef

11.

Biswas DK, Singh S, Shi Q, Pardee AB, Iglehart JD (2005) Crossroads of estrogen receptor and NF-kappaB signaling. Sci STKE 2005:pe27. doi:10.1126/stke.2882005pe27

12.

Buness A, Huber W, Steiner K, Sultmann H, Poustka A (2005) arrayMagic: two-colour cDNA microarray quality control and preprocessing. Bioinformatics 21:554–556. doi:10.1093/bioinformatics/bti052 PubMedCrossRef

13.

Cardoso F, Van’t Veer L, Rutgers E, Loi S, Mook S, Piccart-Gebhart MJ (2008) Clinical application of the 70-gene profile: the MINDACT trial. J Clin Oncol 26:729–735. doi:10.1200/JCO.2007.14.3222 PubMedCrossRef

14.

Clamp A, Danson S, Clemons M (2002) Hormonal risk factors for breast cancer: identification, chemoprevention, and other intervention strategies. Lancet Oncol 3:611–619. doi:10.1016/S1470-2045(02)00875-6 PubMedCrossRef

15.

Coussens LM, Werb Z (2002) Inflammation and cancer. Nature 420(6917):860–867. doi:10.1038/nature01322 PubMedCrossRef

16.

Cox DR (1972) Regression models and life tables. J R Stat Soc [Ser A], 187–220

17.

de Visser KE, Eichten A, Coussens LM (2006) Paradoxical roles of the immune system during cancer development. Nat Rev Cancer 6:24–37. doi:10.1038/nrc1782 PubMedCrossRef

18.

DeNardo DG, Coussens LM (2007) Inflammation and breast cancer. Balancing immune response: crosstalk between adaptive and innate immune cells during breast cancer progression. Breast Cancer Res 9:212. doi:10.1186/bcr1746

19.

Diehn M, Sherlock G, Binkley G, Jin H, Matese JC, Hernandez-Boussard T et al (2003) SOURCE: a unified genomic resource of functional annotations, ontologies, and gene expression data. Nucleic Acids Res 31:219–223. doi:10.1093/nar/gkg014 PubMedCrossRef

20.

Edgar R, Domrachev M, Lash AE (2002) Gene expression omnibus: NCBI gene expression and hybridization array data repository. Nucleic Acids Res 30:207–210. doi:10.1093/nar/30.1.207 PubMedCrossRef

21.

Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pages C et al (2006) Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 313:1960–1964. doi:10.1126/science.1129139 PubMedCrossRef

22.

Griffith CD, Ellis IO, Bell J, Burns K, Blamey RW (1990) Density of lymphocytic infiltration of primary breast cancer does not affect short-term disease-free interval or survival. J R Coll Surg Edinb 35:289–292PubMed

23.

Hayes DF (2005) Prognostic and predictive factors revisited. Breast 14:493–499. doi:10.1016/j.breast.2005.08.023 PubMedCrossRef

24.

Hochberg Y, Benjamini Y (1990) More powerful procedures for multiple significance testing. Stat Med 9:811–818. doi:10.1002/sim.4780090710 PubMedCrossRef

25.

Kreike B, van Kouwenhove M, Horlings H, Weigelt B, Peterse H, Bartelink H et al (2007) Gene expression profiling and histopathological characterization of triple-negative/basal-like breast carcinomas. Breast Cancer Res 9:R65. doi:10.1186/bcr1771

26.

Lash AE, Tolstoshev CM, Wagner L, Schuler GD, Strausberg RL, Riggins GJ et al (2000) SAGEmap: a public gene expression resource. Genome Res 10:1051–1060. doi:10.1101/gr.10.7.1051 PubMedCrossRef

27.

Marques LA, Franco EL, Torloni H, Brentani MM, da Silva-Neto JB, Brentani RR (1990) Independent prognostic value of laminin receptor expression in breast cancer survival. Cancer Res 50:1479–1483PubMed

28.

McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM (2005) Reporting recommendations for tumor marker prognostic studies (REMARK). J Natl Cancer Inst 97:1180–1184PubMedCrossRef

29.

Menard S, Tomasic G, Casalini P, Balsari A, Pilotti S, Cascinelli N et al (1997) Lymphoid infiltration as a prognostic variable for early-onset breast carcinomas. Clin Cancer Res 3:817–819PubMed

30.

Miller LD, Smeds J, George J, Vega VB, Vergara L, Ploner A et al (2005) An expression signature for p53 status in human breast cancer predicts mutation status, transcriptional effects, and patient survival. Proc Natl Acad Sci USA 102:13550–13555. doi:10.1073/pnas.0506230102 PubMedCrossRef

31.

Nixon AJ, Neuberg D, Hayes DF, Gelman R, Connolly JL, Schnitt S et al (1994) Relationship of patient age to pathologic features of the tumor and prognosis for patients with stage I or II breast cancer. J Clin Oncol 12:888–894PubMed

32.

Oldford SA, Robb JD, Codner D, Gadag V, Watson PH, Drover S (2006) Tumor cell expression of HLA-DM associates with a Th1 profile and predicts improved survival in breast carcinoma patients. Int Immunol 18:1591–1602. doi:10.1093/intimm/dxl092 PubMedCrossRef

33.

Rilke F, Colnaghi MI, Cascinelli N, Andreola S, Baldini MT, Bufalino R et al (1991) Prognostic significance of HER-2/neu expression in breast cancer and its relationship to other prognostic factors. Int J Cancer 49:44–49. doi:10.1002/ijc.2910490109 PubMedCrossRef

34.

Schlingemann J, Thuerigen O, Ittrich C, Toedt G, Kramer H, Hahn M et al (2005) Effective transcriptome amplification for expression profiling on sense-oriented oligonucleotide microarrays. Nucleic Acids Res 33:e29. doi:10.1093/nar/gni029

35.

Smyth GK (2004) Linear models and empirical bayes methods for assessing differential expression in microarray experiments Stat Appl Genet Mol Biol 3:Article3

36.

Sorlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H et al (2001) Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA 98:10869–10874. doi:10.1073/pnas.191367098 PubMedCrossRef

37.

Sotiriou C, Neo SY, McShane LM, Korn EL, Long PM, Jazaeri A et al (2003) Breast cancer classification and prognosis based on gene expression profiles from a population-based study. Proc Natl Acad Sci USA 100:10393–10398. doi:10.1073/pnas.1732912100 PubMedCrossRef

38.

Teschendorff AE, Journee M, Absil PA, Sepulchre R, Caldas C (2007) Elucidating the altered transcriptional programs in breast cancer using independent component analysis. PLOS Comput Biol 3:e161. doi:10.1371/journal.pcbi.0030161

39.

Teschendorff AE, Miremadi A, Pinder SE, Ellis IO, Caldas C (2007) An immune response gene expression module identifies a good prognosis subtype in estrogen receptor negative breast cancer. Genome Biol 8:R157. doi:10.1186/gb-2007-8-8-r157

40.

van‘t Veer LJ, Dai H, van de Vijver MJ, He YD, Hart AA, Mao M et al (2002) Gene expression profiling predicts clinical outcome of breast cancer. Nature 415:530–536. doi:10.1038/415530a

41.

van de Vijver MJ, He YD, van’t Veer LJ, Dai H, Hart AA, Voskuil DW et al (2002) A gene-expression signature as a predictor of survival in breast cancer. N Engl J Med 347:1999–2009. doi:10.1056/NEJMoa021967 PubMedCrossRef

42.

West RB, Nuyten DS, Subramanian S, Nielsen TO, Corless CL, Rubin BP et al (2005) Determination of stromal signatures in breast carcinoma. PLoS Biol 3:e187. doi:10.1371/journal.pbio.0030187

43.

Whitford P, Mallon EA, George WD, Campbell AM (1990) Flow cytometric analysis of tumour infiltrating lymphocytes in breast cancer. Br J Cancer 62:971–975PubMed

44.

Yao C, Lin Y, Ye CS, Bi J, Zhu YF, Wang SM (2007) Role of interleukin-8 in the progression of estrogen receptor-negative breast cancer. Chin Med J (Engl) 120:1766–1772

Title: Effects of infiltrating lymphocytes and estrogen receptor on gene expression and prognosis in breast cancer
Authors: Alberto Calabrò
Tim Beissbarth
Ruprecht Kuner
Michael Stojanov
Axel Benner
Martin Asslaber
Ferdinand Ploner
Kurt Zatloukal
Hellmut Samonigg
Annemarie Poustka
Holger Sültmann
Publication date: 01-07-2009
Publisher: Springer US
Published in: Breast Cancer Research and Treatment / Issue 1/2009
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-008-0105-3

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

At a glance: The STEP trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 1/2009

Matrix metalloproteinase-1 promotes breast cancer angiogenesis and osteolysis in a novel in vivo model

Cognitive impairments associated with breast cancer treatments: results from a longitudinal study

Biologic therapy of breast cancer: focus on co-inhibition of endocrine and angiogenesis pathways

The prognostic significance of Ki67 before and after neoadjuvant chemotherapy in breast cancer

Clinical significance of axillary nodal ratio in stage II/III breast cancer treated with neoadjuvant chemotherapy

Pharmaceuticals that cause mammary gland tumors in animals: findings in women

Keynote webinar | Spotlight on antibody–drug conjugates in cancer