title: Interleukin-6 receptor in spindle-shaped stromal cells, a prognostic determinant of early breast cancer.
abstract: 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.
authors.affiliation: Laboratorio de Inmunohematología, Instituto de Biología y Medicina Experimental (IBYME) - Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Vuelta de Obligado 2490, CP 1428, Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina.
authors.forename: Vivian
authors.initials: V
authors.lastname: Labovsky
authors.affiliation: Laboratorio de Inmunohematología, Instituto de Biología y Medicina Experimental (IBYME) - Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Vuelta de Obligado 2490, CP 1428, Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina.
authors.forename: Leandro Marcelo
authors.initials: LM
authors.lastname: Martinez
authors.affiliation: Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Junín 954, CP 1113, Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina.
authors.forename: María de Luján
authors.initials: ML
authors.lastname: Calcagno
authors.affiliation: Departamento de Anatomía Patológica, Hospital Italiano, Juan Domingo Perón 4190, CP 1181, Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina.
authors.forename: Kevin Mauro
authors.initials: KM
authors.lastname: Davies
authors.affiliation: Departamento de Anatomía Patológica, Hospital Italiano, Juan Domingo Perón 4190, CP 1181, Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina.
authors.forename: Hernán
authors.initials: H
authors.lastname: García-Rivello
authors.affiliation: Departamento de Anatomía Patológica, Hospital Italiano, Juan Domingo Perón 4190, CP 1181, Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina.
authors.forename: Alejandra
authors.initials: A
authors.lastname: Wernicke
authors.affiliation: Departamento de Trasplante de Medula Ósea, Fundación Favaloro, Solís 443, CP 1428, Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Feldman
authors.affiliation: Laboratorio de Inmunohematología, Instituto de Biología y Medicina Experimental (IBYME) - Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Vuelta de Obligado 2490, CP 1428, Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina.
authors.forename: María Belén
authors.initials: MB
authors.lastname: Giorello
authors.affiliation: Laboratorio de Inmunohematología, Instituto de Biología y Medicina Experimental (IBYME) - Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Vuelta de Obligado 2490, CP 1428, Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina.
authors.forename: Ayelén
authors.initials: A
authors.lastname: Matas
authors.affiliation: Laboratorio de Inmunohematología, Instituto de Biología y Medicina Experimental (IBYME) - Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Vuelta de Obligado 2490, CP 1428, Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina.
authors.forename: Francisco Raúl
authors.initials: FR
authors.lastname: Borzone
authors.affiliation: University of Memphis, 3720 Alumni Ave, 38152, Memphis, TN, USA.
authors.forename: Scott C
authors.initials: SC
authors.lastname: Howard
authors.affiliation: Laboratorio de Inmunohematología, Instituto de Biología y Medicina Experimental (IBYME) - Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Vuelta de Obligado 2490, CP 1428, Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina. achasseing@ibyme.conicet.gov.ar.
authors.forename: Norma Alejandra
authors.initials: NA
authors.lastname: Chasseing
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D060787:Neoplasm Grading; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D011379:Prognosis; D019947:Receptors, Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism; D017154:Stromal Cells / Q000378:metabolism* / Q000473:pathology; D047368:Tumor Burden; D053319:Tumor Necrosis Factor Decoy Receptors / Q000235:genetics / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D019947:Receptors, Interleukin-6; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; C505639:TNFRSF10B protein, human; C451501:TNFRSF10D protein, human; D053319:Tumor Necrosis Factor Decoy Receptors
keywords: Breast cancer; Cancer-associated fibroblasts; Interleukin-6 receptor; Mesenchymal stem cells; Spindle-shaped stromal cells