Caracterización de la implicación de la proteína APRIL en el cáncer de mama

• Autores: Araceli García Castro
• Directores de la Tesis: Lourdes Planelles Carazo (dir. tes.)
• Lectura: En la Universidad Autónoma de Madrid ( España ) en 2012
• Idioma: español
• Tribunal Calificador de la Tesis: Isabel Mérida De San Román (presid.), Juan Manuel Zapata Hernández (secret.), Guadalupe Sabio Buzo (voc.), Eva González Suárez (voc.), Miguel Martín Giménez (voc.)
• Materias:
  • Ciencias de la vida
    • Biología molecular
• Enlaces
  • Tesis en acceso abierto en: Biblos-e Archivo
• Resumen

  • APRIL is a protein belonging to the tumour necrosis factor (TNF) ligand family that is expressed by immune cells and cells outside the immune system like osteoclasts, epithelial and mesenchymal stem cells. Moreover, high levels of APRIL mRNA and protein have been found in hematopoietic malignancies such us leukaemia and lymphoma and correlate with disease progression. In breast carcinoma and other solid tumours, immunohistochemistry analysis has shown that APRIL is expressed, although the role of this cytokine in tumour development, maintenance or progression is still unclear. In this study we aim to investigate the implication of APRIL in breast cancer using various experimental models.

    We described that four human breast carcinoma cell lines (MDA-MB-231, MDA-MB-468, T47-D and MCF-7) express APRIL and its receptors, BCMA and TACI, at different levels, and that inflammatory stimuli enhance APRIL secretion. We studied the APRIL effect on cell growth and found that addition of recombinant APRIL increases cell proliferation in the four cell lines. siRNA experiments confirmed this result and indicated that endogenous APRIL sustains basal cell proliferation through both receptors. We also investigated the signalling pathways implicated and found that APRIL activates AKT and the MAP-Kinases p38 and ERK1/2.

    To examine the influence of APRIL in breast cancer in vivo, we used two approaches. We generated MMTV-neu/APRIL double transgenic (Tg) mice and saw no differences in tumour onset but an increment in tumour growth (volume) and a reduced tumour free survival in double-Tg compared to MMTV-neu-Tg mice. We also carried on a syngeneic tumour transplant model injecting 4T1 tumour cells in APRIL-Tg and wild-type (WT) control mice. We found that tumour growth is enhanced in mice over- expressing APRIL compared to WT animals. In addition, analysis of 4T1 tumours revealed the presence of APRIL inside the tumours and a higher proliferation rate (Ki67 positive area) in mice carrying APRIL transgene.

    We finally analysed human primary breast carcinoma tissue samples and saw that APRIL is expressed and correlates positively with tumour grade. TACI and BCMA are also present but we have not found a clear expression pattern yet.

    Taken together, our results provide evidence of APRIL, BCMA and TACI expression in breast cancer. We also described a proliferation-promoting role of APRIL both in vitro and in vivo, and showed that this effect is mediated by AKT-, ERK- and p38-pathways.