Prognostic significance of S100A4-expression and subcellular localization in early-stage breast cancer
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Prognostic factors are useful in order to identify early-stage breast cancer patients who might benefit from adjuvant treatment. The metastasis-promoting protein S100A4 has previously been associated with poor prognosis in breast cancer patients. The protein is expressed in diverse subcellular compartments, including the cytoplasm, extracellular space, and nucleus. Nuclear expression is an independent predictor of poor outcome in several cancer types, but the significance of subcellular expression has not yet been assessed in breast cancer.
Nuclear and cytoplasmic expression of S100A4 was assessed by immunohistochemistry in prospectively collected tumor samples from early-stage breast cancer patients using tissue microarrays.
In patients not receiving adjuvant systemic therapy, nuclear or cytoplasmic expression was found in 44/291 tumors (15%). Expression of either nuclear or cytoplasmic S100A4 was associated with histological grade III, triple-negative subtype, and Ki-67-expression. Patients with S100A4-positive tumors had inferior metastasis-free and overall survival compared to S100A4-negative. When expression was analyzed separately, nuclear S100A4 was a significant predictor of outcome, while cytoplasmic was not. In patients who received adjuvant treatment 23/300 tumors (8%) were S100A4-positive, but no tumors displayed nuclear staining alone. S100A4-expression was strongly associated with histological grade III and triple-negative subtype. Although not significant, metastasis-free and overall survival was numerically reduced in patients with S100A4-positive tumors.
S100A4-expression was associated with poor outcome in early-stage breast cancer, but the low percentage of positive tumors and the modest survival differences imply that the clinical utility in selection of patients for adjuvant treatment is limited.
KeywordsBreast cancer S100A4 Nuclear localization Prognostic marker
We would like to thank Elisabeth Emilsen for excellent technical assistance.
This work was supported by the Cancer Society of Norway (Project no [#4218523581] to EVE).
People involved in the Oslo Breast Cancer Consortium (group authorship)
Torill Sauer, Jürgen Geisler, Solveig Hofvind, Tone F Bathen, Elin Borgen, Anne‐Lise Børresen‐Dale, Olav Engebråten, Øystein Fodstad, Øystein Garred, Gry A Geitvik, Rolf Kåresen, Bjørn Naume, Gunhild M Mælandsmo, Hege G Russnes, Ellen Schlichting, Therese Sørlie, Ole C Lingjærde, Vessela N Kristensen, Kristine K Sahlberg, Helle K Skjerven, Britt Fritzman.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interests.
The project was approved by the Regional Ethics Committee of South-East Norway, and all procedures performed were in accordance with their ethical standards and with the 1964 Helsinki declaration and its later amendments.
Written informed consent was obtained from all patients enrolled in the study.
- 1.Clarke M, Collins R, Darby S, Davies C, Elphinstone P, Evans V, Godwin J, Gray R, Hicks C, James S, MacKinnon E, McGale P, McHugh T, Peto R, Taylor C, Wang Y (2005) Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials. Lancet (London, England) 366(9503):2087–2106. doi: 10.1016/s0140-6736(05)67887-7
- 4.Sack U, Walther W, Scudiero D, Selby M, Aumann J, Lemos C, Fichtner I, Schlag PM, Shoemaker RH, Stein U (2011) S100A4-induced cell motility and metastasis is restricted by the Wnt/beta-catenin pathway inhibitor calcimycin in colon cancer cells. Mol Biol Cell 22(18):3344–3354. doi: 10.1091/mbc.E10-09-0739 CrossRefPubMedPubMedCentralGoogle Scholar
- 6.Dahlmann M, Okhrimenko A, Marcinkowski P, Osterland M, Herrmann P, Smith J, Heizmann CW, Schlag PM, Stein U (2014) RAGE mediates S100A4-induced cell motility via MAPK/ERK and hypoxia signaling and is a prognostic biomarker for human colorectal cancer metastasis. Oncotarget 5(10):3220–3233CrossRefPubMedPubMedCentralGoogle Scholar
- 7.Ambartsumian N, Klingelhofer J, Grigorian M, Christensen C, Kriajevska M, Tulchinsky E, Georgiev G, Berezin V, Bock E, Rygaard J, Cao R, Cao Y, Lukanidin E (2001) The metastasis-associated Mts1(S100A4) protein could act as an angiogenic factor. Oncogene 20(34):4685–4695. doi: 10.1038/sj.onc.1204636 CrossRefPubMedGoogle Scholar
- 10.Bjornland K, Winberg JO, Odegaard OT, Hovig E, Loennechen T, Aasen AO, Fodstad O, Maelandsmo GM (1999) S100A4 involvement in metastasis: deregulation of matrix metalloproteinases and tissue inhibitors of matrix metalloproteinases in osteosarcoma cells transfected with an anti-S100A4 ribozyme. Cancer Res 59(18):4702–4708PubMedGoogle Scholar
- 11.Schmidt-Hansen B, Ornas D, Grigorian M, Klingelhofer J, Tulchinsky E, Lukanidin E, Ambartsumian N (2004) Extracellular S100A4(mts1) stimulates invasive growth of mouse endothelial cells and modulates MMP-13 matrix metalloproteinase activity. Oncogene 23(32):5487–5495. doi: 10.1038/sj.onc.1207720 CrossRefPubMedGoogle Scholar
- 14.Bettum IJ, Vasiliauskaite K, Nygaard V, Clancy T, Pettersen SJ, Tenstad E, Maelandsmo GM, Prasmickaite L (2014) Metastasis-associated protein S100A4 induces a network of inflammatory cytokines that activate stromal cells to acquire pro-tumorigenic properties. Cancer Lett 344(1):28–39. doi: 10.1016/j.canlet.2013.10.036 CrossRefPubMedGoogle Scholar
- 16.Hoshino A, Costa-Silva B, Shen TL, Rodrigues G, Hashimoto A, Tesic Mark M, Molina H, Kohsaka S, Di Giannatale A, Ceder S, Singh S, Williams C, Soplop N, Uryu K, Pharmer L, King T, Bojmar L, Davies AE, Ararso Y, Zhang T, Zhang H, Hernandez J, Weiss JM, Dumont-Cole VD, Kramer K, Wexler LH, Narendran A, Schwartz GK, Healey JH, Sandstrom P, Jorgen Labori K, Kure EH, Grandgenett PM, Hollingsworth MA, de Sousa M, Kaur S, Jain M, Mallya K, Batra SK, Jarnagin WR, Brady MS, Fodstad O, Muller V, Pantel K, Minn AJ, Bissell MJ, Garcia BA, Kang Y, Rajasekhar VK, Ghajar CM, Matei I, Peinado H, Bromberg J, Lyden D (2015) Tumour exosome integrins determine organotropic metastasis. Nature. doi: 10.1038/nature15756 PubMedPubMedCentralGoogle Scholar
- 17.Ilg EC, Schafer BW, Heizmann CW (1996) Expression pattern of S100 calcium-binding proteins in human tumors. Int J Cancer 68(3):325–332. doi: 10.1002/(sici)1097-0215(19961104)68:3<325:aid-ijc10>3.0.co;2-7 CrossRefPubMedGoogle Scholar
- 20.de Silva Rudland S, Martin L, Roshanlall C, Winstanley J, Leinster S, Platt-Higgins A, Carroll J, West C, Barraclough R, Rudland P (2006) Association of S100A4 and osteopontin with specific prognostic factors and survival of patients with minimally invasive breast cancer. Clin Cancer Res 12(4):1192–1200. doi: 10.1158/1078-0432.ccr-05-1580 CrossRefGoogle Scholar
- 23.Boye K, Nesland JM, Sandstad B, Maelandsmo GM, Flatmark K (2010) Nuclear S100A4 is a novel prognostic marker in colorectal cancer. Eur J Cancer (Oxford, England: 1990) 46(16):2919–2925. doi: 10.1016/j.ejca.2010.07.013
- 24.Flatmark K, Pedersen KB, Nesland JM, Rasmussen H, Aamodt G, Mikalsen SO, Bjornland K, Fodstad O, Maelandsmo GM (2003) Nuclear localization of the metastasis-related protein S100A4 correlates with tumour stage in colorectal cancer. J Pathol 200(5):589–595. doi: 10.1002/path.1381 CrossRefPubMedGoogle Scholar
- 25.Fabris L, Cadamuro M, Moserle L, Dziura J, Cong X, Sambado L, Nardo G, Sonzogni A, Colledan M, Furlanetto A, Bassi N, Massani M, Cillo U, Mescoli C, Indraccolo S, Rugge M, Okolicsanyi L, Strazzabosco M (2011) Nuclear expression of S100A4 calcium-binding protein increases cholangiocarcinoma invasiveness and metastasization. Hepatology (Baltimore, Md) 54(3):890–899. doi: 10.1002/hep.24466
- 26.Kikuchi N, Horiuchi A, Osada R, Imai T, Wang C, Chen X, Konishi I (2006) Nuclear expression of S100A4 is associated with aggressive behavior of epithelial ovarian carcinoma: an important autocrine/paracrine factor in tumor progression. Cancer Sci 97(10):1061–1069. doi: 10.1111/j.1349-7006.2006.00295.x CrossRefPubMedGoogle Scholar
- 28.Naume B, Borgen E, Kvalheim G, Karesen R, Qvist H, Sauer T, Kumar T, Nesland JM (2001) Detection of isolated tumor cells in bone marrow in early-stage breast carcinoma patients: comparison with preoperative clinical parameters and primary tumor characteristics. Clin Cancer Res 7(12):4122–4129PubMedGoogle Scholar
- 29.Wiedswang G, Borgen E, Karesen R, Kvalheim G, Nesland JM, Qvist H, Schlichting E, Sauer T, Janbu J, Harbitz T, Naume B (2003) Detection of isolated tumor cells in bone marrow is an independent prognostic factor in breast cancer. J Clin Oncol 21(18):3469–3478. doi: 10.1200/jco.2003.02.009 CrossRefPubMedGoogle Scholar
- 30.Synnestvedt M, Borgen E, Russnes HG, Kumar NT, Schlichting E, Giercksky KE, Karesen R, Nesland JM, Naume B (2013) Combined analysis of vascular invasion, grade, HER2 and Ki67 expression identifies early breast cancer patients with questionable benefit of systemic adjuvant therapy. Acta Oncol (Stockholm, Sweden) 52(1):91–101. doi: 10.3109/0284186x.2012.713508
- 31.Flatmark K, Maelandsmo GM, Mikalsen SO, Nustad K, Varaas T, Rasmussen H, Meling GI, Fodstad O, Paus E (2004) Immunofluorometric assay for the metastasis-related protein S100A4: release of S100A4 from normal blood cells prohibits the use of S100A4 as a tumor marker in plasma and serum. Tumour Biol 25(1–2):31–40. doi: 10.1159/000077721 CrossRefPubMedGoogle Scholar
- 32.Boye K, Jacob H, Frikstad KA, Nesland JM, Maelandsmo GM, Dahl O, Nesbakken A, Flatmark K (2016) Prognostic significance of S100A4 expression in stage II and III colorectal cancer: results from a population-based series and a randomized phase III study on adjuvant chemotherapy. Cancer Med 5(8):1840–1849. doi: 10.1002/cam4.766 CrossRefPubMedPubMedCentralGoogle Scholar
- 36.Heizmann CW (2002) The multifunctional S100 protein family. Methods Mol Biol (Clifton, NJ) 172:69–80. doi: 10.1385/1-59259-183-3:069
- 37.Egeland EV, Boye K, Pettersen SJ, Haugen MH, Oyjord T, Malerod L, Flatmark K, Maelandsmo GM (2015) Enrichment of nuclear S100A4 during G2/M in colorectal cancer cells: possible association with cyclin B1 and centrosomes. Clin Exp Metastasis 32(8):755–767. doi: 10.1007/s10585-015-9742-1 CrossRefPubMedGoogle Scholar
- 38.Cadamuro M, Spagnuolo G, Sambado L, Indraccolo S, Nardo G, Rosato A, Brivio S, Caslini C, Stecca T, Massani M, Bassi N, Novelli E, Spirli C, Fabris L, Strazzabosco M (2016) Low-dose paclitaxel reduces S100A4 nuclear import to inhibit invasion and hematogenous metastasis of cholangiocarcinoma. Cancer Res 76(16):4775–4784. doi: 10.1158/0008-5472.can-16-0188 CrossRefPubMedGoogle Scholar
- 40.Bouris P, Skandalis SS, Piperigkou Z, Afratis N, Karamanou K, Aletras AJ, Moustakas A, Theocharis AD, Karamanos NK (2015) Estrogen receptor alpha mediates epithelial to mesenchymal transition, expression of specific matrix effectors and functional properties of breast cancer cells. Matrix Biol 43:42–60. doi: 10.1016/j.matbio.2015.02.008 CrossRefPubMedGoogle Scholar
- 42.Grum-Schwensen B, Klingelhofer J, Beck M, Bonefeld CM, Hamerlik P, Guldberg P, Grigorian M, Lukanidin E, Ambartsumian N (2015) S100A4-neutralizing antibody suppresses spontaneous tumor progression, pre-metastatic niche formation and alters T-cell polarization balance. BMC Cancer 15:44. doi: 10.1186/s12885-015-1034-2 CrossRefPubMedPubMedCentralGoogle Scholar