“role of p38 mapk in breast cancer
- Autores: Begoña Cánovas Bilbao
- Directores de la Tesis: Ángel Rodríguez Nebreda (dir. tes.), Isabel Fabregat Romero (tut. tes.)
- Lectura: En la Universitat de Barcelona ( España ) en 2017
- Idioma: español
- Tribunal Calificador de la Tesis: Neus Agell Jané (presid.), Violeta Serra Elizalde (secret.), Juan Méndez Zunzunegui (voc.)
- Programa de doctorado: Programa de Doctorado en Biomedicina por la Universidad de Barcelona
- Materias:
- Enlaces
- Tesis en acceso abierto en: TDX
- Resumen
Cancer refers to a group of diseases characterized by the presence of cells that divide uncontrollably and have the ability to spread to other tissues.
During the past years, the protein kinase p38α has emerged as an important regulator of tumorigenesis that often functions as a tumor suppressor in normal epithelial cells. However, recent studies provided evidence for a function of p38α promoting tumor cell proliferation and survival in some cancer types. Moreover, p38α inhibition has been shown to cooperate with chemotherapeutic drugs such as cisplatin and sorafenib. Given that the role of p38α in cancer seems to be cell and context dependent, in this work we have addressed the function of p38α in the particular context of breast cancer progression.
Using the Polyoma middle T mammary tumorigenesis model, we have found that p38α expression in epithelial cancer cells is essential for tumor cell survival. In order to analyze the underlying molecular mechanisms, we established cell lines from the PyMT-induced mammary tumors. We observed that p38α downregulation resulted in replication stress, elevated DNA damage, and increased chromosome missegregation, which correlated with decreased viability of the PyMT-expressing cancer cells.
The defects in replication fork progression and the increased DNA damage led us to investigate the status of the DNA damage response in p38α-deficient cancer cells. We observed impaired single strand-DNA generation, ATR activation and RAD51 recruitment after DNA damage, indicating that homologous recombination DNA repair was defective in p38α deficient cells. Moreover, we identified CtIP, a key factor that promotes DNA-end resection in mammalian cells, as a p38α substrate. De-regulation of CtIP due to decreased p38α-mediated phosphorylation is likely to affect the DNA damage response and explain many of the observed phenotypes. Altogether, our results indicated that p38α was required for effective DNA damage response and repair, which in turn impinged on proper DNA replication and maintenance of chromosome stability in breast cancer epithelial cells.
The above results suggested that targeting p38α could increase tumor cell sensitivity to chromosome instability-inducing agents such as taxanes. We confirmed this hypothesis using both PyMT-induced tumors and patient-derived xenografts, in which p38α inhibitors enhanced, accelerated or prolonged the anti-tumoral response observed with the taxanes alone.
In summary, we describe a novel role of p38α in coordinating the DNA damage response and limiting chromosome instability in cancer cells, and propose the combination of p38α inhibitors and taxanes as a potential therapeutic option in breast cancer treatment.
