ERK1/2 inhibition increases antiestrogen treatment efficacy by interfering with hypoxia-induced downregulation of ERα: a combination therapy potentially targeting hypoxic and dormant tumor cells

Tumor hypoxia is associated with cancer invasiveness, metastasis and treatment failure. Recent data suggest that the major target for endocrine treatment in breast cancer, ERα, is downregulated during hypoxia, but the mechanism behind this remains unknown. MAPK signaling as well as ERα regulation has earlier been independently linked to hypoxia and we now demonstrate HIF-1α and ERK1/2-activation in vivo towards the necrotic zone in DCIS of the breast, parallel with ERα downregulation. Hypoxia further caused transcriptional downregulation of ERα via activation of ERK1/2 in cell lines and, importantly, MEK1/2 inhibitors (U0126 or PD184352) or ERK1/2 suppression by siRNA partially restored the ERα expression. U0126 combined with tamoxifen accordingly produced an increased efficacy of the anti-estrogens during hypoxia. Based on these findings, we suggest a promising novel therapy for ERα-positive breast cancer where a combination of endocrine treatment and ERK1/2 inhibitors may increase treatment response by improved targeting of dormant hypoxic tumor cells.