Study of genetic factors determining the heterogeneous activation of signaling pathways associated with cardiac pathophysiology and their contribution to the individual susceptibility to cardiotoxicity caused by chemotherapy

Abstract

The cardiotoxicity of anthracyclines is a complex trait. The degree of cardiac damage is in part mediated by an imbalance between different intracellular signaling pathways such as p38MAPK or PI3K / AKT which at the same time, have been described as being important in other processes of cardiac tissue. Working hypothesis: (i) Interindividual differences in cardiac levels of signaling pathways may contribute to the different susceptibility among patients to cardiac damage produced by anthracyclines (ii) Identification of genomic regions associated with different levels of these signaling proteins is a strategy to identify part of the genetic component of cardiotoxicity. [Material and methods]: We studied 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. Histopathological parameters of cardiac damage were quantified using the Ariol automated 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) The genetic background influences the activation of heart intracellular signaling pathways. (ii) The levels of activation of these pathways are correlated with histopathological parameters of heart damage. (iii) There are specific and common genetic regions of susceptibility of complex trait (QTL) associated with both processes. [Conclusion]: We used the levels of different intramyocardial signaling pathways as intermediate phenotypes for the identification of part of the genetic component of susceptibility to heart damage caused by chemotherapy. These results will require further validation to be later transferred to the human population.