1. ¹Division of Pathology, Department of Laboratory Medicine, Lund University, Malmö University Hospital, S-205 02, Malmö, Sweden
2. ²Division of Molecular Medicine, Department of Laboratory Medicine, Lund University, Malmö University Hospital, S-205 02, Malmö, Sweden

Correspondence: G Landberg, Division of Pathology, Department of Laboratory Medicine, Lund University, Malmö University Hospital, S-205 02, Malmö, Sweden. E-mail: goran.landberg@pat.mas.lu.se

Received 29 June 2004; Revised 14 April 2005; Accepted 11 May 2005; Published online 27 June 2005.

Abstract

Tumor hypoxia is associated with cancer invasiveness, metastasis and treatment failure. Recent data suggest that the major target for endocrine treatment in breast cancer, ER, is downregulated during hypoxia, but the mechanism behind this remains unknown. MAPK signaling as well as ER regulation has earlier been independently linked to hypoxia and we now demonstrate HIF-1 and ERK1/2-activation in vivo towards the necrotic zone in DCIS of the breast, parallel with ER downregulation. Hypoxia further caused transcriptional downregulation of ER 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 ER 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 ER-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.