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; Hedenfalk, Ingrid; Nilsson, Elise; Påhlman, Sven; Landberg, Göran

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.

Mark

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)

Please use this url to cite or link to this publication: https://lup.lub.lu.se/record/142222

author

Kronblad, Åsa ^LU ; Hedenfalk, Ingrid ^LU

; Nilsson, Elise ^LU ; Påhlman, Sven ^LU and Landberg, Göran ^LU

organization

publishing date

2005

type

Contribution to journal

publication status

published

subject

Cancer and Oncology

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
pmid:16007158

ISSN

1476-5594

DOI

10.1038/sj.onc.1208830

language

English

LU publication?

yes

additional info

The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Molecular Medicine (013031200), Pathology (Malmö) (013031000), Oncology, MV (013035000)

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

2016-04-01 12:09:28

date last changed

2022-01-26 23:36:23

@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}},
  keywords     = {{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}},
  doi          = {{10.1038/sj.onc.1208830}},
  volume       = {{24}},
  year         = {{2005}},
}

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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.