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  3. Non-canonical NF-kappa B pathway activation predicts outcome in borderline oestrogen receptor positive breast carcinoma

Non-canonical NF-kappa B pathway activation predicts outcome in borderline oestrogen receptor positive breast carcinoma

Fecha de publicación:

Autores de IIS La Fe

Participantes ajenos a IIS La Fe

  • Rojo, F
  • Gonzalez-Perez, A
  • Furriol, J
  • Nicolau, MJ
  • Burgues, O
  • Sabbaghi, M
  • Gonzalez-Navarrete, I
  • Cristobal, I
  • Serrano, L
  • Zazo, S
  • Madoz, J
  • Servitja, S
  • Tusquets, I
  • Albanell, J
  • Lluch, A
  • Rovira, A
  • Eroles, P

Abstract

Background: NF-kappa B signalling appears deregulated in breast tumours. The purpose of this study was to determine whether the non-canonical NF-kappa B pathway, is activated in oestrogen receptor positive (ER+) breast cancer, to identify any correlation between its activity and the clinico-pathological phenotype and to explore whether NF-kappa B2 and RelB subunits and/or any of their target genes might be used as a predictive marker. Methods: Two independent cohorts of ER+ early breast cancer patients treated with adjuvant endocrine therapy were included in the study. Activation of RelB and NF-kappa B2 subunits was determined in a training set of 121 patients by measuring DNA-binding activities in nuclear extracts from fresh frozen specimens by an ELISA-based assay. Samples of 15 ER - breast cancer patients were also included in the study. In a large validation cohort of 207 patients, nuclear immunostaining of RelB and NF-kappa B2 on formalin-fixed paraffin-embedded specimens was performed. Statistical correlation within clinico-pathological factors, disease-free survival (DFS) and overall survival (OS) was evaluated. Publicly available gene expression and survival data have been interrogated aimed to identify target genes. Results: Activation of NF-kappa B2 and RelB was found in 53.7 and 49.2% of the 121 ER+ tumours analysed, with similar levels to ER - breast tumours analysed in parallel for comparisons. In the validation cohort, we obtained a similar proportion of cases with activation of NF-kappa B2 and RelB (59.9 and 32.4%), with a 39.6% of co-activation. Multiplexing immunofluorescence in breast cancer tissue confirmed an inverse spatial distribution of ER with NF-kappa B2 and RelB nuclear expression in tumour cells. Interestingly, NF-kappa B2 and RelB mRNA expression was inversely correlated with ER gene (ESR1) levels (P<0.001, both) and its activation was significantly associated with worse DFS (P = 0.005 and P = 0.035, respectively) in ER+ breast cancer. Moreover, the co-activation of both subunits showed a stronger association with early relapse (P = 0.002) and OS (P = 0.001). Finally, higher expression of the non-canonical NF-kappa B target gene myoglobin was associated with a poor outcome in ER+ breast cancer (DFS, P<0.05). Conclusions: The non-canonical NF-kappa B pathway activation is inversely associated with oestrogen receptor expression in ER+ breast cancer and predicts poor survival in this subgroup. The myoglobin gene expression has been identified as a possible surrogate marker of the non-canonical NF-kappa B pathway activation in these tumours.

Datos de la publicación

ISSN/ISSNe:
0007-0920, 1532-1827

BRITISH JOURNAL OF CANCER  NATURE PUBLISHING GROUP

Tipo:
Article
Páginas:
322-331
Factor de Impacto:
3,030 SCImago ℠
Cuartil:
Q1 SCImago ℠

Citas Recibidas en Web of Science: 17

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Keywords

  • breast cancer; NF-kappa B; non-canonical; ER-positive

Campos de estudio

Proyectos asociados

PAPEL DEL FACTOR DE CRECIMIENTO PLACENTARIO EN EL MANEJO DE LA PREECLAMPSIA NO SEVERA: ESTUDIO ALEATORIZADO

Investigador Principal: ALFREDO JOSÉ PERALES MARÍN

PI15/01935 . INSTITUTO DE SALUD CARLOS III . 2016

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