Breast Cancer Research and Treatment

, Volume 145, Issue 2, pp 307–315 | Cite as

RANK expression as a prognostic and predictive marker in breast cancer

  • Berit Maria Pfitzner
  • Daniel Branstetter
  • Sibylle Loibl
  • Carsten Denkert
  • Bianca Lederer
  • Wolfgang Daniel Schmitt
  • Frank Dombrowski
  • Martin Werner
  • Thomas Rüdiger
  • William C. Dougall
  • Gunter von Minckwitz
Preclinical study


RANK ligand (RANKL) is crucial for the development of mouse mammary glands during pregnancy. RANKL functions as a major paracrine effector of the mitogenic action of progesterone in mammary epithelium via its receptor RANK and has a role in expansion and regenerative potential of mammary stem cells. Pharmacologic inhibition of RANKL attenuates the development of mammary carcinoma and inhibits metastatic progression in multiple mouse models. Primary breast carcinoma samples from the neoadjuvant GeparTrio study were analyzed to correlate the expression of human RANK and RANKL with pathological complete response (pCR), disease-free (DFS), and overall (OS) survival. Pre-treatment FFPE core biopsies (n = 601) were analyzed for percentage and intensity of immunohistochemical RANK and RANKL expression. Antibodies against human RANK (N-1H8; Amgen) and human RANKL (M366; Amgen) were used. RANK protein was expressed in 160 (27 %) patients. Increased RANK expression was observed in 14.5 % of patients and correlated with high tumor grade (p < 0.023) and negative hormone receptor (HR) status (p < 0.001). Patients with high RANK expression showed a higher pCR rate (23.0 % vs. 12.6 %, p = 0.010), shorter DFS (p = 0.038), and OS (p = 0.011). However, prognostic and predictive information was not an independent parameter. Only 6 % of samples expressed RANKL, which was not correlated with any clinical features. Higher RANK expression in the primary tumor is associated with a higher sensitivity to chemotherapy, but also a higher risk of relapse and death. Our study provides a basis for further exploration of the antitumor activity of clinical antibodies against RANKL.


RANK Breast cancer Denosumab Immunohistochemistry 



We would like to thank Ms. Ines Koch and Ms. Britta Beyer for their excellent technical assistance as well as Ms. Britta Dahl for proofreading.

Conflict of interest

D.B. declares that he receives remuneration as an employee of Amgen, Inc. and got stock ownership in Amgen, Inc.. S.L. declares to be a consultant/advisory role of Amgen. M.W. declares to be a consultant/advisory role of DAKO and he receives funding from DAKO and Biotest. W.C.D. declares that he receives remuneration as an employee of Amgen, Inc., got stock ownership in Amgen, Inc. and receives funding from Amgen, Inc.. G.V.M. declares that he receives remuneration of Amgen, Inc. and receives funding from Amgen, Inc.. The other author’s declare that they have no conflict of interest.

Ethical Standard

The experiments comply with the current laws of the country in which they were performed.


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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Berit Maria Pfitzner
    • 1
    • 10
  • Daniel Branstetter
    • 2
  • Sibylle Loibl
    • 3
    • 11
  • Carsten Denkert
    • 1
    • 10
  • Bianca Lederer
    • 3
  • Wolfgang Daniel Schmitt
    • 1
    • 10
  • Frank Dombrowski
    • 4
  • Martin Werner
    • 5
    • 8
  • Thomas Rüdiger
    • 6
  • William C. Dougall
    • 7
  • Gunter von Minckwitz
    • 3
    • 9
  1. 1.Institute of Pathology, Campus MitteCharité University Hospital BerlinBerlinGermany
  2. 2.Department of PathologyAmgen Inc.SeattleUSA
  3. 3.German Breast GroupNeu-IsenburgGermany
  4. 4.Institute of PathologyErnst-Moritz-Arnd-University GreifswaldGreifswaldGermany
  5. 5.Department of PathologyUniversity Hospital FreiburgFreiburgGermany
  6. 6.Institute of PathologyHospital KarlsruheKarlsruheGermany
  7. 7.Therapeutic Innovation UnitAmgen Inc.SeattleUSA
  8. 8.German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ)HeidelbergGermany
  9. 9.University Women’s Hospital FrankfurtFrankfurtGermany
  10. 10.DKTK Side Charité BerlinGerman Cancer Consortium (DKTK)BerlinGermany
  11. 11.Gynecological Hospital Sana Klinikum OffenbachOffenbach am MainGermany

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