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Expression pattern of stromal cell-derived factor-1 chemokine in invasive breast cancer is correlated with estrogen receptor status and patient prognosis

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Abstract

Chemokine receptor CXCR4 is known to be crucially involved in tumor progression, but the role of its ligand, stromal cell-derived factor-1 (SDF-1), remains unclear. The present study was conducted to clarify the clinicopathological and prognostic impact of SDF-1 expression in invasive breast cancers. Expression of SDF-1 mRNA and protein was examined in five breast cancer cell lines with or without estradiol treatment. In 52 surgically resected breast cancers, the level of SDF-1 mRNA in frozen samples and the pattern of SDF-1 protein immunoreactivity in formalin-fixed paraffin-embedded tissue sections were compared. In another cohort of 223 breast cancers, the correlation between SDF-1 immunoreactivity and clinicopathological parameters was examined using a tissue microarray. Estradiol treatment markedly increased the expression of SDF-1 mRNA and protein in the estrogen receptor (ER)-positive cell lines, MCF-7 and T47D. Among the 52 resected breast cancers, those with a cytoplasmic-dominant pattern of SDF-1 expression showed higher SDF-1 mRNA levels (median 27.4) than those with a membrane-dominant or negative pattern (median 13.6, P = 0.0017). Accordingly, the cytoplasmic-dominant pattern was defined as “high SDF-1 expression,” and other patterns were defined as “low SDF-1 expression.” Among the cohort of 223 tumors, “high SDF-1 expression” was detected in 158 (70.9%) and was significantly correlated with ER positivity (P < 0.0001), HER2 negativity (P = 0.021), and lower grade (P < 0.0001). Univariate analysis demonstrated that “high SDF-1 expression” was a significant indicator of better clinical outcome in both the entire patient cohort (P = 0.017) and the 133 patients with ER-positive tumors (P = 0.036), but not in the 90 patients with ER-negative tumors. Multivariate analysis showed that SDF-1 status was an independent factor related to overall survival in patients with ER-positive tumors (P = 0.046). SDF-1 status is a significant prognostic factor and may be clinically useful for assigning adjuvant therapy to patients with ER-positive invasive breast cancers.

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Abbreviations

SDF-1:

Stromal cell-derived factor-1

ERG:

Estrogen-regulated gene

TMA:

Tissue microarray

ER:

Estrogen receptor alpha

PR:

Progesterone receptor

References

  1. Marugame T, Matsuda T, Kamo K, Katanoda K, Ajiki W, Sobue T (2007) Cancer incidence and incidence rates in Japan in 2001 based on the data from 10 population-based cancer registries. Jpn J Clin Oncol 37(11):884–891

    Article  PubMed  Google Scholar 

  2. Yoshimoto M, Tada K, Hori H et al (2004) Improvement in the prognosis of Japanese breast cancer patients from 1946 to 2001—an institutional review. Jpn J Clin Oncol 34(8):457–462

    Article  PubMed  Google Scholar 

  3. EBCTCG (2005) Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 365(9472):1687–1717

    Article  Google Scholar 

  4. Ciocca DR, Elledge R (2000) Molecular markers for predicting response to tamoxifen in breast cancer patients. Endocrine 13(1):1–10

    Article  CAS  PubMed  Google Scholar 

  5. Goldhirsch A, Wood WC, Gelber RD, Coates AS, Thurlimann B, Senn HJ (2007) Progress and promise: highlights of the international expert consensus on the primary therapy of early breast cancer. Ann Oncol 18(7):1133–1144

    Article  CAS  PubMed  Google Scholar 

  6. Hall JM, Korach KS (2003) Stromal cell-derived factor 1, a novel target of estrogen receptor action, mediates the mitogenic effects of estradiol in ovarian and breast cancer cells. Mol Endocrinol 17(5):792–803

    Article  CAS  PubMed  Google Scholar 

  7. Tashiro K, Tada H, Heilker R, Shirozu M, Nakano T, Honjo T (1993) Signal sequence trap: a cloning strategy for secreted proteins and type I membrane proteins. Science 261(5121):600–603

    Article  CAS  PubMed  Google Scholar 

  8. Nagasawa T, Kikutani H, Kishimoto T (1994) Molecular cloning and structure of a pre-B-cell growth-stimulating factor. Proc Natl Acad Sci USA 91(6):2305–2309

    Article  CAS  PubMed  Google Scholar 

  9. Burger JA, Kipps TJ (2006) CXCR4: a key receptor in the crosstalk between tumor cells and their microenvironment. Blood 107(5):1761–1767

    Article  CAS  PubMed  Google Scholar 

  10. Kulbe H, Levinson NR, Balkwill F, Wilson JL (2004) The chemokine network in cancer—much more than directing cell movement. Int J Dev Biol 48(5–6):489–496

    Article  CAS  PubMed  Google Scholar 

  11. Shinto E, Tsuda H, Ueno H et al (2005) Prognostic implication of laminin-5 gamma 2 chain expression in the invasive front of colorectal cancers, disclosed by area-specific four-point tissue microarrays. Lab Invest 85(2):257–266

    Article  CAS  PubMed  Google Scholar 

  12. Muller A, Homey B, Soto H et al (2001) Involvement of chemokine receptors in breast cancer metastasis. Nature 410(6824):50–56

    Article  CAS  PubMed  Google Scholar 

  13. Barbero S, Bonavia R, Bajetto A et al (2003) Stromal cell-derived factor 1alpha stimulates human glioblastoma cell growth through the activation of both extracellular signal-regulated kinases 1/2 and Akt. Cancer Res 63(8):1969–1974

    CAS  PubMed  Google Scholar 

  14. Kijima T, Maulik G, Ma PC et al (2002) Regulation of cellular proliferation, cytoskeletal function, and signal transduction through CXCR4 and c-Kit in small cell lung cancer cells. Cancer Res 62(21):6304–6311

    CAS  PubMed  Google Scholar 

  15. Yoon Y, Liang Z, Zhang X et al (2007) CXC chemokine receptor-4 antagonist blocks both growth of primary tumor and metastasis of head and neck cancer in xenograft mouse models. Cancer Res 67(15):7518–7524

    Article  CAS  PubMed  Google Scholar 

  16. Chinni SR, Sivalogan S, Dong Z et al (2006) CXCL12/CXCR4 signaling activates Akt-1 and MMP-9 expression in prostate cancer cells: the role of bone microenvironment-associated CXCL12. Prostate 66(1):32–48

    Article  CAS  PubMed  Google Scholar 

  17. Ehtesham M, Winston JA, Kabos P, Thompson RC (2006) CXCR4 expression mediates glioma cell invasiveness. Oncogene 25(19):2801–2806

    Article  CAS  PubMed  Google Scholar 

  18. Fernandis AZ, Prasad A, Band H, Klosel R, Ganju RK (2004) Regulation of CXCR4-mediated chemotaxis and chemoinvasion of breast cancer cells. Oncogene 23(1):157–167

    Article  CAS  PubMed  Google Scholar 

  19. Retz MM, Sidhu SS, Blaveri E et al (2005) CXCR4 expression reflects tumor progression and regulates motility of bladder cancer cells. Int J Cancer 114(2):182–189

    Article  CAS  PubMed  Google Scholar 

  20. Orimo A, Gupta PB, Sgroi DC et al (2005) Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell 121(3):335–348

    Article  CAS  PubMed  Google Scholar 

  21. Pan J, Mestas J, Burdick MD et al (2006) Stromal derived factor-1 (SDF-1/CXCL12) and CXCR4 in renal cell carcinoma metastasis. Mol Cancer 5:56

    Article  PubMed  Google Scholar 

  22. Ottaiano A, Franco R, Aiello Talamanca A et al (2006) Overexpression of both CXC chemokine receptor 4 and vascular endothelial growth factor proteins predicts early distant relapse in stage II-III colorectal cancer patients. Clin Cancer Res 12(9):2795–2803

    Article  CAS  PubMed  Google Scholar 

  23. Kato M, Kitayama J, Kazama S, Nagawa H (2003) Expression pattern of CXC chemokine receptor-4 is correlated with lymph node metastasis in human invasive ductal carcinoma. Breast Cancer Res 5(5):R144–R150

    Article  CAS  PubMed  Google Scholar 

  24. Cabioglu N, Yazici MS, Arun B et al (2005) CCR7 and CXCR4 as novel biomarkers predicting axillary lymph node metastasis in T1 breast cancer. Clin Cancer Res 11(16):5686–5693

    Article  CAS  PubMed  Google Scholar 

  25. Kim J, Takeuchi H, Lam ST et al (2005) Chemokine receptor CXCR4 expression in colorectal cancer patients increases the risk for recurrence and for poor survival. J Clin Oncol 23(12):2744–2753

    Article  CAS  PubMed  Google Scholar 

  26. Spano JP, Andre F, Morat L et al (2004) Chemokine receptor CXCR4 and early-stage non-small cell lung cancer: pattern of expression and correlation with outcome. Ann Oncol 15(4):613–617

    Article  PubMed  Google Scholar 

  27. Rempel SA, Dudas S, Ge S, Gutierrez JA (2000) Identification and localization of the cytokine SDF1 and its receptor, CXC chemokine receptor 4, to regions of necrosis and angiogenesis in human glioblastoma. Clin Cancer Res 6(1):102–111

    CAS  PubMed  Google Scholar 

  28. Brand S, Dambacher J, Beigel F et al (2005) CXCR4 and CXCL12 are inversely expressed in colorectal cancer cells and modulate cancer cell migration, invasion and MMP-9 activation. Exp Cell Res 310(1):117–130

    Article  CAS  PubMed  Google Scholar 

  29. Zagzag D, Krishnamachary B, Yee H et al (2005) Stromal cell-derived factor-1alpha and CXCR4 expression in hemangioblastoma and clear cell-renal cell carcinoma: von Hippel-Lindau loss-of-function induces expression of a ligand and its receptor. Cancer Res 65(14):6178–6188

    Article  CAS  PubMed  Google Scholar 

  30. Salmaggi A, Gelati M, Pollo B et al (2005) CXCL12 expression is predictive of a shorter time to tumor progression in low-grade glioma: a single-institution study in 50 patients. J Neurooncol 74(3):287–293

    Article  CAS  PubMed  Google Scholar 

  31. Yoshitake N, Fukui H, Yamagishi H et al (2008) Expression of SDF-1 alpha and nuclear CXCR4 predicts lymph node metastasis in colorectal cancer. Br J Cancer 98(10):1682–1689

    Article  CAS  PubMed  Google Scholar 

  32. Ishigami S, Natsugoe S, Okumura H et al (2007) Clinical implication of CXCL12 expression in gastric cancer. Ann Surg Oncol 14(11):3154–3158

    Article  PubMed  Google Scholar 

  33. Uchida D, Onoue T, Tomizuka Y et al (2007) Involvement of an autocrine stromal cell derived factor-1/CXCR4 system on the distant metastasis of human oral squamous cell carcinoma. Mol Cancer Res 5(7):685–694

    Article  CAS  PubMed  Google Scholar 

  34. Wendt MK, Cooper AN, Dwinell MB (2008) Epigenetic silencing of CXCL12 increases the metastatic potential of mammary carcinoma cells. Oncogene 27(10):1461–1471

    Article  CAS  PubMed  Google Scholar 

  35. Wendt MK, Drury LJ, Vongsa RA, Dwinell MB (2008) Constitutive CXCL12 expression induces anoikis in colorectal carcinoma cells. Gastroenterology 135(2):508–517

    Article  CAS  PubMed  Google Scholar 

  36. Gilbert DC, Chandler I, McIntyre A et al (2009) Clinical and biological significance of CXCL12 and CXCR4 expression in adult testes and germ cell tumours of adults and adolescents. J Pathol 217(1):94–102

    Article  CAS  PubMed  Google Scholar 

  37. Rae JM, Johnson MD, Scheys JO, Cordero KE, Larios JM, Lippman ME (2005) GREB 1 is a critical regulator of hormone dependent breast cancer growth. Breast Cancer Res Treat 92(2):141–149

    Article  CAS  PubMed  Google Scholar 

  38. Frasor J, Danes JM, Komm B, Chang KC, Lyttle CR, Katzenellenbogen BS (2003) Profiling of estrogen up- and down-regulated gene expression in human breast cancer cells: insights into gene networks and pathways underlying estrogenic control of proliferation and cell phenotype. Endocrinology 144(10):4562–4574

    Article  CAS  PubMed  Google Scholar 

  39. Pattarozzi A, Gatti M, Barbieri F et al (2008) 17beta-estradiol promotes breast cancer cell proliferation-inducing stromal cell-derived factor-1-mediated epidermal growth factor receptor transactivation: reversal by gefitinib pretreatment. Mol Pharmacol 73(1):191–202

    Article  CAS  PubMed  Google Scholar 

  40. Yoshida N, Omoto Y, Inoue A et al (2004) Prediction of prognosis of estrogen receptor-positive breast cancer with combination of selected estrogen-regulated genes. Cancer Sci 95(6):496–502

    Article  CAS  PubMed  Google Scholar 

  41. Ceradini DJ, Kulkarni AR, Callaghan MJ et al (2004) Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1. Nat Med 10(8):858–864

    Article  CAS  PubMed  Google Scholar 

  42. Nakayama T, Mutsuga N, Tosato G (2007) Effect of fibroblast growth factor 2 on stromal cell-derived factor 1 production by bone marrow stromal cells and hematopoiesis. J Natl Cancer Inst 99(3):223–235

    Article  CAS  PubMed  Google Scholar 

  43. Yang S, Pham LK, Liao CP, Frenkel B, Reddi AH, Roy-Burman P (2008) A novel bone morphogenetic protein signaling in heterotypic cell interactions in prostate cancer. Cancer Res 68(1):198–205

    Article  CAS  PubMed  Google Scholar 

  44. Pils D, Pinter A, Reibenwein J et al (2007) In ovarian cancer the prognostic influence of HER2/neu is not dependent on the CXCR4/SDF-1 signalling pathway. Br J Cancer 96(3):485–491

    Article  CAS  PubMed  Google Scholar 

  45. Haribabu B, Richardson RM, Fisher I et al (1997) Regulation of human chemokine receptors CXCR4. Role of phosphorylation in desensitization and internalization. J Biol Chem 272(45):28726–28731

    Article  CAS  PubMed  Google Scholar 

  46. Fischer T, Nagel F, Jacobs S et al (2008) Reassessment of CXCR4 chemokine receptor expression in human normal and neoplastic tissues using the novel rabbit monoclonal antibody UMB-2. PLoS One 3(12):e4069

    Article  PubMed  Google Scholar 

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Acknowledgments

We thank Dr. Yumi Miyazaki and Ms. Kozue Suzuki for technical assistance and Dr. Keiichi Iwaya for helpful discussion. This work was supported by grants from the Ministry of Defense, Japan, the Ministry of Health, Labor, and Welfare, Japan, the Princess Takamatsu Cancer Research Fund, and the Foundation for Promotion of Defense Medicine.

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Authors and Affiliations

  1. Department of Basic Pathology, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan

    Takayuki Kobayashi, Hitoshi Tsuda, Ryoko Kikuchi & Osamu Matsubara

  2. Department of Surgery, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan

    Tomoyuki Moriya, Shigeto Ueda, Jiro Omata & Junji Yamamoto

  3. Department of General Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan

    Tamio Yamasaki

  4. Pathology Section, Clinical Laboratory Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan

    Hitoshi Tsuda

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  1. Takayuki Kobayashi
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Correspondence to Hitoshi Tsuda.

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Kobayashi, T., Tsuda, H., Moriya, T. et al. Expression pattern of stromal cell-derived factor-1 chemokine in invasive breast cancer is correlated with estrogen receptor status and patient prognosis. Breast Cancer Res Treat 123, 733–745 (2010). https://doi.org/10.1007/s10549-009-0672-y

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  • DOI: https://doi.org/10.1007/s10549-009-0672-y

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