GH enhances breast cancer chemoresistance by inhibiting JNK-mediated apoptosis

GH and insulin-like growth factor 1 (IGF1) are known to promote breast carcinogenesis. Breast cancer (BC) incidence in not increased in female acromegalic patients, but mortality is greater as compared to general population. We previously demonstrated that GH/IGF1 excess influences BC response to therapy, possibly accounting for the increased mortality. We indeed showed that GH and IGF1 induce cell proliferation of a BC cell line, the MCF7 cells, providing protection towards the cytotoxic effects of doxorubicin (D). GH effects are direct and not mediated by IGF1, since they are apparent also in the presence of an IGF1 receptor blocking antibody and disappear in the presence of the GH receptor antagonist Pegvisomant (Peg). The aim of the present study was to evaluate the possible mechanisms implicated in the protective action of GH towards the cytotoxic effects of D in the BC cell line, MCF7. We investigated the combined effects of GH and D on MCF7 cell cycle, apoptosis, glutathione-S transferase (GST) activity and JNK transcriptional activity. We found that GH does not revert D-induced accumulation of MCF7 cells in G2/M phase of the cell cycle. However, GH significantly reduced both basal and D-induced MCF7 cell apoptosis, an effect nearly completely blocked by Peg. We therefore explored the involvement of GST, which activation protects DNA against damage by anticancer drugs. However, GH treatment significantly reduced GST activity in MCF7 cells, as well as Peg, possibly indicating a greater susceptibility of Peg-treated cells to DNA damage. In addition, GH reduced basal and D-stimulated JNK transcriptional activity. These data altogether indicate that GH directly induces resistance to chemotherapic drugs by protecting the cells from apoptosis by reducing JNK transcriptional activity. Our data further support the hypothesis that GH excess might hamper BC treatment, possibly resulting in an increased mortality.