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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.

Kronblad, Åsa LU ; Hedenfalk, Ingrid LU ; Nilsson, Elise LU ; Påhlman, Sven LU and Landberg, Göran LU (2005) In Oncogene 24(45). p.6835-6841
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 alpha, is downregulated during hypoxia, but the mechanism behind this remains unknown. MAPK signaling as well as ER alpha regulation has earlier been independently linked to hypoxia and we now demonstrate HIF-1 alpha and ERK1/2-activation in vivo towards the necrotic zone in DCIS of the breast, parallel with ER alpha downregulation. Hypoxia further caused transcriptional downregulation of ER alpha 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 ERa expression. U0126... (More)
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 alpha, is downregulated during hypoxia, but the mechanism behind this remains unknown. MAPK signaling as well as ER alpha regulation has earlier been independently linked to hypoxia and we now demonstrate HIF-1 alpha and ERK1/2-activation in vivo towards the necrotic zone in DCIS of the breast, parallel with ER alpha downregulation. Hypoxia further caused transcriptional downregulation of ER alpha 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 ERa expression. U0126 combined with tamoxifen accordingly produced an increased efficacy of the anti-estrogens during hypoxia. Base don these findings, we suggest a promising novel therapy for ER alpha-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. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
hypoxia, MAPK, breast cancer, ERK1/2, tamoxifen, ER alpha
in
Oncogene
volume
24
issue
45
pages
6835 - 6841
publisher
Nature Publishing Group
external identifiers
  • pmid:16007158
  • wos:000232527800011
  • scopus:27144501505
ISSN
1476-5594
DOI
10.1038/sj.onc.1208830
language
English
LU publication?
yes
id
f8f78161-4dfc-4842-8239-cae747ca7836 (old id 142222)
alternative location
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=16007158&dopt=Abstract
date added to LUP
2007-07-25 15:25:46
date last changed
2017-04-09 03:37:39
@article{f8f78161-4dfc-4842-8239-cae747ca7836,
  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 alpha, is downregulated during hypoxia, but the mechanism behind this remains unknown. MAPK signaling as well as ER alpha regulation has earlier been independently linked to hypoxia and we now demonstrate HIF-1 alpha and ERK1/2-activation in vivo towards the necrotic zone in DCIS of the breast, parallel with ER alpha downregulation. Hypoxia further caused transcriptional downregulation of ER alpha 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 ERa expression. U0126 combined with tamoxifen accordingly produced an increased efficacy of the anti-estrogens during hypoxia. Base don these findings, we suggest a promising novel therapy for ER alpha-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.},
  author       = {Kronblad, Åsa and Hedenfalk, Ingrid and Nilsson, Elise and Påhlman, Sven and Landberg, Göran},
  issn         = {1476-5594},
  keyword      = {hypoxia,MAPK,breast cancer,ERK1/2,tamoxifen,ER alpha},
  language     = {eng},
  number       = {45},
  pages        = {6835--6841},
  publisher    = {Nature Publishing Group},
  series       = {Oncogene},
  title        = {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.},
  url          = {http://dx.doi.org/10.1038/sj.onc.1208830},
  volume       = {24},
  year         = {2005},
}