ERK1/2 inhibition increases antiestrogen treatment efficacy by interfering with hypoxia-induced downregulation of ERalpha: 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, ERalpha, is downregulated during hypoxia, but the mechanism behind this remains unknown. MAPK signaling as well as ERalpha regulation has earlier been independently linked to hypoxia and we now demonstrate HIF-1alpha and ERK1/2-activation in vivo towards the necrotic zone in DCIS of the breast, parallel with ERalpha downregulation. Hypoxia further caused transcriptional downregulation of ERalpha 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 ERalpha 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 ERalpha-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.
Kronblad
Asa
A
Division of Pathology, Department of Laboratory Medicine, Lund University, Malmö University Hospital, S-205 02, Malmö, Sweden.
Hedenfalk
Ingrid
I
Nilsson
Elise
E
Påhlman
Sven
S
Landberg
Göran
G
D001549:Benzamides / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D002070:Butadienes / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D015687:Cell Hypoxia; D015536:Down-Regulation; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D020847:Estrogen Receptor Modulators / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors*; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors*; D009570:Nitriles / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D013629:Tamoxifen / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*
C120227:2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluorobenzamide; D001549:Benzamides; D002070:Butadienes; D004791:Enzyme Inhibitors; D020847:Estrogen Receptor Modulators; D047628:Estrogen Receptor alpha; D009570:Nitriles; C113580:U 0126; D013629:Tamoxifen; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3