Identification of common genetic determinants of cell signalling pathways and cardiotoxicity by anthracyclines and taxanes

Introduction: The cardiotoxicity of anthracyclines is a complex trait. The level of cardiac damage is partly mediated by an imbalance between different intracellular signalling pathways, such as p38MAPK or PI3K / AKT, which at the same time, have been described as being important in other cardiac tissue processes.

Working hypothesis: (i) Inter-individual differences in cardiac levels of signalling proteins may contribute to the different susceptibility of patients to cardiac damage produced by anthracyclines. (ii) Identification of genomic regions associated with different levels of these signalling proteins.

Material and methods: A study was conducted using a cohort of mice with ERBB2 + breast cancer generated by a backcross between two syngeneic strains, C56BL/6 and FVB (carrier of the transgene MMTV-ErbB2 / Neu). The animals were treated with doxorubicin alone or in combination with docetaxel. Cardiac damage was quantified at histopathological level using the Ariol™ system. Levels of the following proteins were quantified by Luminex: pCREB (Ser133), pAKT (Ser473), pSTAT5A / B (Tyr694 / Tyr699), pSTAT3 (Ser707), p70S6K (Thr412), p38 MAPK (Thr180 / Tyr182), pJNK (Thr183 / Tyr185), NFKB (Ser536), and pERK1 / 2 (Thr185 / Tyr187).

Results: (i) Inter-individual variability to heart damage caused by doxorubicin plus / minus docetaxel. (ii) Quantification of the cardiac levels of some components of the signalling pathways. (iii) Identification of regions of susceptibility of complex trait QTL.

Conclusion: Use is made of the levels of different intracellular intra-myocardial signalling pathways as intermediate phenotypes for the identification of part of the susceptibility to heart damage. These results will require further validation to be able to be transferred to the human population.