Tumor Biology

, Volume 37, Issue 10, pp 13377–13384 | Cite as

Interleukin-6 receptor in spindle-shaped stromal cells, a prognostic determinant of early breast cancer

  • Vivian Labovsky
  • Leandro Marcelo Martinez
  • María de Luján Calcagno
  • Kevin Mauro Davies
  • Hernán García-Rivello
  • Alejandra Wernicke
  • Leonardo Feldman
  • María Belén Giorello
  • Ayelén Matas
  • Francisco Raúl Borzone
  • Scott C. Howard
  • Norma Alejandra Chasseing
Original Article


Spindle-shaped stromal cells, like carcinoma-associated fibroblasts and mesenchymal stem cells, influence tumor behavior and can serve as parameters in the clinical diagnosis, therapy, and prognosis of early breast cancer. Therefore, the aim of this study is to explore the clinicopathological significance of tumor necrosis factor-related apoptosis-induced ligand (TRAIL) receptors (Rs) 2 and 4 (TRAIL-R2 and R4), and interleukin-6 R (IL-6R) in spindle-shaped stromal cells, not associated with the vasculature, as prognostic determinants of early breast cancer patients. Receptors are able to trigger the migratory activity, among other functions, of these stromal cells. We conducted immunohistochemical analysis for the expression of these receptors in spindle-shaped stromal cells, not associated with the vasculature, of primary tumors from early invasive breast cancer patients, and analyzed their association with clinicopathological characteristics. Here, we demonstrate that the elevated levels of TRAIL-R2, TRAIL-R4, and IL-6R in these stromal cells were significantly associated with a higher risk of metastatic occurrence (p = 0.034, 0.026, and 0.006; respectively). Moreover, high expression of TRAIL-R4 was associated with shorter disease-free survival and metastasis-free survival (p = 0.013 and 0.019; respectively). Also, high expression of IL-6R was associated with shorter disease-free survival, metastasis-free survival, and overall survival (p = 0.003, 0.001, and 0.003; respectively). Multivariate analysis showed that IL-6R expression was an independent prognostic factor for disease-free survival and metastasis-free survival (p = 0.035). This study is the first to demonstrate that high levels of IL-6R expression in spindle-shaped stromal cells, not associated with the vasculature, could be used to identify early breast cancer patients with poor outcomes.


Breast cancer Cancer-associated fibroblasts Interleukin-6 receptor Mesenchymal stem cells Spindle-shaped stromal cells 



The authors thank the Pathology Department of Italian Hospital for the help with tumor sample collection. This research was supported by grants from the National Agency of Scientific and Technological Promotion (FONCYT PICT 2006-01915), Argentina; Grant PIP2011 (166) from the National Council of Scientific and Technical Research CONICET (PIP 2011/2013), Argentina; Roemmers Foundation (2009–2011), Argentina, and Florencio Fiorini Foundation (2013), Argentina, and René Barón Foundation (2015), Argentina.

Compliance with ethical standards

Ethical standards

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Moreover, we have obtained a statement of informed consent to publish from the participant (or legal parent or guardian for children) to report individual patient data.

Conflicts of interest



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Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2016

Authors and Affiliations

  • Vivian Labovsky
    • 1
  • Leandro Marcelo Martinez
    • 1
  • María de Luján Calcagno
    • 2
  • Kevin Mauro Davies
    • 3
  • Hernán García-Rivello
    • 3
  • Alejandra Wernicke
    • 3
  • Leonardo Feldman
    • 4
  • María Belén Giorello
    • 1
  • Ayelén Matas
    • 1
  • Francisco Raúl Borzone
    • 1
  • Scott C. Howard
    • 5
  • Norma Alejandra Chasseing
    • 1
  1. 1.Laboratorio de Inmunohematología, Instituto de Biología y Medicina Experimental (IBYME) - Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)Buenos AiresArgentina
  2. 2.Facultad de Farmacia y BioquímicaUniversidad de Buenos AiresBuenos AiresArgentina
  3. 3.Departamento de Anatomía PatológicaHospital ItalianoBuenos AiresArgentina
  4. 4.Departamento de Trasplante de Medula ÓseaFundación FavaloroBuenos AiresArgentina
  5. 5.University of MemphisMemphisUSA

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