Breast Cancer Research and Treatment

, Volume 87, Issue 2, pp 157–166 | Cite as

Elevated Concentrations of Serum Relaxin are Associated with Metastatic Disease in Breast Cancer Patients

  • C. Binder
  • A. Simon
  • L. Binder
  • Th. Hagemann
  • M. Schulz
  • G. Emons
  • L. Trümper
  • A. Einspanier


Relaxin (RLX) is known to induce remodeling of benign stromal tissues through upregulation of matrix metalloproteases (MMPs). Recently, we could show that RLX also induces MMPs in breast cancer cells and enhances in vitro invasiveness. To investigate its potential role for progression of breast cancer in vivo, RLX serum concentrations were determined in 160 breast cancer patients during post-surgical follow-up. RLX concentrations in cancer patients were significantly higher than in a control population of healthy blood donors and patients with various other diseases (0.47 versus 0.29 ng/ml, p < 0.0001). There was a significant difference between patients with metastases (0.62 ng/ml) and those without (0.38ng/ml, p < 0.0001). Overall survival was shorter in RLX-positive ( > 0.4ng/ml) than in RLX-negative patients (p= 0.016). Cox regression analysis showed that RLX was not an independent variable, in contrast to metastatic disease and primary lymph node involvement. Taken together, the detection of elevated RLX concentrations especially in patients with metastases supports the assumption that there is a role for RLX in tissue remodeling during breast cancer progression.

breast cancer CA 15-3 metastasis relaxin survival 


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  1. 1.
    Bani D:Relaxin:a pleiotropic hormone.Gen Pharmacol 28:13–22,1997Google Scholar
  2. 2.
    Min G, Hartzog MG, Jennings RL, Winn RJ, Sherwood OD:Evidence that endogenous relaxin promotes growth of the vagina and uterus during pregnancy in gilts.Endocrinology 138:560–565,1997Google Scholar
  3. 3.
    Zhao I, Roche PJ, Gunnersen JM, Hammond VE, Tregear GW, Wintour EM, Beck F:Mice without a functional relaxin gene are unable to deliver milk to their pups. Endocrinology 140:445–453,1999Google Scholar
  4. 4.
    Unemori EN, Amento EP:Relaxin modulates synthesis and secretion of procollagenase and collagen by human dermal broblasts.J Biol Chem 265:10681–10685,1990Google Scholar
  5. 5.
    Garber SL, Mirochnik Y, Brecklin CS, Unemori EN, Singh AK, Slobodskoy L, Grove BH, Anunda JA, Dunea G: Relaxin decreases renal interstitial brosis and slows progression of renal disease.Kidney Int 59:876–882,2001Google Scholar
  6. 6.
    Williams EJ, Benyon RC, Trim N, Hadwin R, Grove BH, Arthur MJ, Unemori EN, Iredale JP:Relaxin inhibits effective collagen deposition by cultured hepatic stellate cells and decreases rat liver brosis.Gut 49:577–583, 2001Google Scholar
  7. 7.
    Unemori EN, Lewis M, Constant J, Arnold G, Grove BH, Normand J, Deshpande U, Salles A, Pickford LB, Erikson ME, Hunt TK, Huang X:Relaxin induces vascular endothelial growth factor and angiogenesis selectively at wound sites.Wound Repair Regen 8:361–370,2000Google Scholar
  8. 8.
    Unemori EN, Pickford LB, Salles AL, Piercy CE, Grove BH, Eriksom ME, Amento EP:Relaxin induces an extracellular matrix-degrading phenotype in human lung broblasts in vitro and inhibits lung brosis in a murine model in vivo.J Clin Invest 98:2739–2745,1996Google Scholar
  9. 9.
    Qin X, Chua PK, Ohira RH, Bryan-Greenwood GD:An autocrine/paracrine role of human decidual relaxin.II. Stromelysin-1 (MMP-3)and tissue inhibitor of matrix met-alloproteinase-1 (TIMP-1).Biol Reprod 56:812–820, 1997Google Scholar
  10. 10.
    Kapila S, Xie Y:Targeted induction of collagenase and stromelysin by relaxin in unprimed and beta-estradiolprimed diarthrodial joint brocartilaginous cells but not in synoviocytes.Lab Invest 78:925–938,1998Google Scholar
  11. 11.
    Lenhart JA, Ryan PL, Ohleth K, Palmer SS, Bagnell CA: Relaxin increases secretion of matrix metalloproteinase-2 and matrix metalloproteinase-9 during uterine and cervical growth and remodeling in the pig.Endocrinology 122: 3941–3949,2001Google Scholar
  12. 12.
    Polette M, Nawrocki B, Gilles C, Sato H, Seiki M, Tournier JM, Birembaut P:MT-MMP expression and localisation in human lung and breast cancers.Virchows Arch 428:29–35, 1996Google Scholar
  13. 13.
    Brummer O, Athar S, Riethdorf L, Loning T, Herbst H: Matrix-metalloproteinases 1,2 and 3 and their tissue inhibitors 1 and 2 in benign and malignant breast lesions: an in situ hybridization study.Virchows Arch 435:566–573, 1999Google Scholar
  14. 14.
    Balduyck M, Zerimech F, Goyer V, Lemaire R, Hemon B, Grard G, Thiebaut C, Lemaire V, Dacquembronne E, Duhem T:Specific expression of matrix metalloproteinases 1,3,9 and 13 associated with invasiveness of breast cancer cells in vitro.Clin Exp Metastasis 18:171–178,2000Google Scholar
  15. 15.
    Ramos DeSimone N, Hahn-Dantona E, Sipley J, Nagase H, Frech DL, Quigley JP:Activation of matrix metalloproteinase 9 (MMP-9)via a converging plasmin/stromelysin-1 cascade enhances tumor cell invasion.J Biol Chem 274:13066–13077,1999Google Scholar
  16. 16.
    Talvensaari-Mattila A, Pääkkö P, Höyhtyä M, BlancoSequeiros G, Turpeenniemi-Hujanen T:Matrix metalloproteinase-2 immunoreactive protein:a marker of aggressiveness in breast carcinoma.Cancer 83:1153–1162, 1998Google Scholar
  17. 17.
    Tashima LS, Mazoujian G, Bryant-Greenwood GD:Human relaxin in normal,benign and neoplastic breast tissue. J Mol Endocrinol 12:351–364,1994Google Scholar
  18. 18.
    Binder C, Hagemann Th, Husen B, Schulz M, Einspanier A:Relaxin enhances in vitro invasiveness of breast cancer cell lines by upregulation of matrix metalloproteases.Mol Hum Reprod 8:789–796,2002Google Scholar
  19. 19.
    Einspanier A, Nubbemeyer R, Schlote S, Schumacher M, Ivell R, Fuhrmann K, Marten A:Relaxin in the marmoset monkey:secretion pattern in the ovarian cycle and early pregnancy.Biol Reprod 61:512–520,1999.Google Scholar
  20. 20.
    O'Byrne EM, Flitcraft JF, Sawyer WK, Hochman J, Weiss G, Steinetz BG:Relaxin bioactivity and immunoactivity in human corpora lutea.Endocrinology 102:1641–1644, 1978Google Scholar
  21. 21.
    Bell RJ, Eddie LW, Lester AR, Wood EC, Johnston PD, Niall HD:Relaxin in human pregnancy serum measured with an homologous radioimmunoassay.Obstet Gynecol 69:585–589,1987Google Scholar
  22. 22.
    Silvertown JD, Geddes BJ, Summerlee AJ:Adenovirusmediated expression of human prorelaxin promotes the invasive potential of canine mammary cancer cells.Endocrinology 144:3683–3691,2003Google Scholar
  23. 23.
    Plunkett ER, Gammal EB:The effect of relaxin upon DMBA-induced mammary cancer in female rats.Br J Cancer 21:592–600,1967Google Scholar
  24. 24.
    Sacchi TB, Bani D, Brandi ML, Falchetti A, Bigazzi M: Relaxin influences growth,differentiation and cell-cell adhesion of human breast cancer cells in culture.Int J Cancer 57:129–134,1994Google Scholar
  25. 25.
    Bani D, Flagiello D, Poupon MF, Nistri S, Poirson-Bichat F, Bigazzi M, Bani-Sacchi T:Relaxin promotes differentiation of human breast cancer cells MCF-7 transplanted into nude mice.Virchows Arch 435:509–519,1999Google Scholar
  26. 26.
    Unemori EN, Erikson ME, Rocco SE, Sutherland KM, Parsell DA, Mak J, Grove BH:Relaxin stimulates expression of vascular endothelial growth factor in human endometrial cells in vitro and is associated with menometrorrhagia in women.Hum Reprod 14:800–806,1999Google Scholar
  27. 27.
    Bani D, Failli P, Bello MG, Thiemermann C, Bani-Sacchi T, Bigazzi M, Masini E:Relaxin activates L-arginine-nitric oxide pathway in vascular smooth muscle cells in culture. Hypertension 31:1240–1247,1998Google Scholar
  28. 28.
    Dschietzig T, Richter C, Bartsch C, Laule M, Armbruster FP, Baumann G, Stangl K:The pregnancy hormone relaxin is a player in human heart failure.FASEB J 15:2187–2195, 2001Google Scholar
  29. 29.
    Borthwick G, Borthwick AC, Grant P, MacLennan AH: Relaxin levels in the human:an indicator of target storage and production sites.In:MacLennan AH, Tregear GW, Bryant-Greenwood G (eds)Progress in Relaxin Research. Singapore, World Scientific Publishing,1994,pp 251–260Google Scholar
  30. 30.
    Nardi E, Bigazzi M, Agrimonti F:Relaxin in fribrocystic disease of the mammary gland.In:Bigazzi M, Greenwood FC, Gasparri F (eds)Biology of Relaxin and its Role in the Human.Amsterdam, Excerpta Medica,1983,pp 417–419Google Scholar
  31. 31.
    Hsu SY, Nakabayashi K, Nishi S, Kumagai J, Kudo M, Sherwood OD, Hsueh AJ:Activation of orphan receptors by the hormone relaxin.Science 295:671–674,2002Google Scholar
  32. 32.
    Stearns V, Yamouchi H, Hayes DF:Circulating tumor markers in breast cancer:accepted utilities and novel prospects.Breast Cancer Res Treat 52:239–259,1998Google Scholar

Copyright information

© Kluwer Academic Publishers 2004

Authors and Affiliations

  • C. Binder
    • 1
  • A. Simon
    • 2
  • L. Binder
    • 3
  • Th. Hagemann
    • 2
  • M. Schulz
    • 2
  • G. Emons
    • 2
  • L. Trümper
    • 2
  • A. Einspanier
    • 4
  1. 1.Department of Haematology/OncologyGeorg-August-University, Robert-Koch-Strasse 40, D-37075GöttingenGermany; Tel.:
  2. 2.Department of Haematology/OncologyGeorg-August-University, GöttingenGermany
  3. 3.Department of Clinical ChemistryGeorg-August-University, GöttingenGermany
  4. 4.Institute of Veterinary Phys.-ChemistryUniversity of LeipzigGermany

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