ERBB and steroid hormone pathways in cell proliferation and differentiation

ERBB receptors are central to the development and progression of various tumours, including breast cancer. This study explored the role of ERBB ligands and receptors in basal-like/triple-negative breast cancer (TNBC), which is characterized by high EGFR and low ERBB2/HER2 expression. Using a quasi-normal basal-like/TNBC model, we found that ERBB2 and ERBB3 protein levels increase under anchorage-independent conditions, and their activation by Neuregulin 1 (NRG1) promotes spheroidogenesis, an effect counteracted by ERBB2-neutralizing antibodies. Similar findings were observed in malignant basal-like/TNBC cells, suggesting an oncogenic role for ERBB2/ERBB3 and their potential as therapeutic targets. Additionally, we observed that Neuregulin 4 (NRG4) activation of ERBB4 enhances the efficacy of anti-ERBB2 agents. It is noteworthy, however, that Neuregulin/ERBB2 signalling also plays a pivotal role in heart development and health; therefore, suppressing this pathway with anti-ERBB2 therapies could induce cardiotoxicity. Steroid hormones show a crosstalk with ERBB signalling, but whether they restrain spheroidogenesis induced by Neuregulins in breast cancer cells or their potential interference with cardiac NRG1/ERBB2 pathway leads to cardiotoxicity, warrants further investigations. In this regard, we aimed to investigate the impact of glucocorticoids on cardiomyocyte proliferation and cardiac health during the postnatal period, since in this developmental stage their role remains less defined. We found that corticosterone, the primary rodent glucocorticoid, restricts neonatal murine cardiomyocyte proliferation, whereas cardiomyocyte-specific Glucocorticoid Receptor (GR) deletion enhances it. Notably, GR ablation also improved heart regeneration following cardiac injury in adult mice, an effect mirrored by GR antagonism. Unexpectedly, corticosterone promoted proliferation in GR-ablated cardiomyocytes, likely through Mineralocorticoid Receptor (MR) activation, with preliminary findings identifying MR target genes involved in this proliferative effect. These opposite actions of corticosterone, anti-proliferative via GR and proliferative via MR, were also observed in adult human myocardial tissue, further supporting the importance of GR-MR balance in cardiomyocyte proliferation and cardiac health.