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HIF2α contributes to antiestrogen resistance via positive bilateral crosstalk with EGFR in breast cancer cells.

Alam, Muhammad Wasi LU ; Persson, Camilla LU ; Reinbothe, Susann LU ; Kazi, Julhash U. LU ; Rönnstrand, Lars LU ; Wigerup, Caroline LU ; Ditzel, Henrik J; Lykkesfeldt, Anne E; Påhlman, Sven LU and Jögi, Annika LU (2016) In Oncotarget 7(10). p.50-11238
Abstract
The majority of breast cancers express estrogen receptor α (ERα), and most patients with ERα-positive breast cancer benefit from antiestrogen therapy. The ERα-modulator tamoxifen and ERα-downregulator fulvestrant are commonly employed antiestrogens. Antiestrogen resistance remains a clinical challenge, with few effective treatments available for patients with antiestrogen-resistant breast cancer. Hypoxia, which is intrinsic to most tumors, promotes aggressive disease, with the hypoxia-inducible transcription factors HIF1 and HIF2 regulating cellular responses to hypoxia. Here, we show that the ERα-expressing breast cancer cells MCF-7, CAMA-1, and T47D are less sensitive to antiestrogens when hypoxic. Furthermore, protein and mRNA levels of... (More)
The majority of breast cancers express estrogen receptor α (ERα), and most patients with ERα-positive breast cancer benefit from antiestrogen therapy. The ERα-modulator tamoxifen and ERα-downregulator fulvestrant are commonly employed antiestrogens. Antiestrogen resistance remains a clinical challenge, with few effective treatments available for patients with antiestrogen-resistant breast cancer. Hypoxia, which is intrinsic to most tumors, promotes aggressive disease, with the hypoxia-inducible transcription factors HIF1 and HIF2 regulating cellular responses to hypoxia. Here, we show that the ERα-expressing breast cancer cells MCF-7, CAMA-1, and T47D are less sensitive to antiestrogens when hypoxic. Furthermore, protein and mRNA levels of HIF2α/HIF2A were increased in a panel of antiestrogen-resistant cells, and antiestrogen-exposure further increased HIF2α expression. Ectopic expression of HIF2α in MCF-7 cells significantly decreased sensitivity to antiestrogens, further implicating HIF2α in antiestrogen resistance. EGFR is known to contribute to antiestrogen resistance: we further show that HIF2α drives hypoxic induction of EGFR and that EGFR induces HIF2α expression. Downregulation or inhibition of EGFR led to decreased HIF2α levels. This positive and bilateral HIF2-EGFR regulatory crosstalk promotes antiestrogen resistance and, where intrinsic hypoxic resistance exists, therapy itself may exacerbate the problem. Finally, inhibition of HIFs by FM19G11 restores antiestrogen sensitivity in resistant cells. Targeting HIF2 may be useful for counteracting antiestrogen resistance in the clinic. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Oncotarget
volume
7
issue
10
pages
50 - 11238
publisher
Impact Journals, LLC
external identifiers
  • pmid:26849233
  • scopus:84962010050
ISSN
1949-2553
DOI
10.18632/oncotarget.7167
language
English
LU publication?
yes
id
94798cc0-be9a-429a-b3c9-234dce643801 (old id 8829182)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/26849233?dopt=Abstract
date added to LUP
2016-03-02 09:39:38
date last changed
2017-06-25 04:04:46
@article{94798cc0-be9a-429a-b3c9-234dce643801,
  abstract     = {The majority of breast cancers express estrogen receptor α (ERα), and most patients with ERα-positive breast cancer benefit from antiestrogen therapy. The ERα-modulator tamoxifen and ERα-downregulator fulvestrant are commonly employed antiestrogens. Antiestrogen resistance remains a clinical challenge, with few effective treatments available for patients with antiestrogen-resistant breast cancer. Hypoxia, which is intrinsic to most tumors, promotes aggressive disease, with the hypoxia-inducible transcription factors HIF1 and HIF2 regulating cellular responses to hypoxia. Here, we show that the ERα-expressing breast cancer cells MCF-7, CAMA-1, and T47D are less sensitive to antiestrogens when hypoxic. Furthermore, protein and mRNA levels of HIF2α/HIF2A were increased in a panel of antiestrogen-resistant cells, and antiestrogen-exposure further increased HIF2α expression. Ectopic expression of HIF2α in MCF-7 cells significantly decreased sensitivity to antiestrogens, further implicating HIF2α in antiestrogen resistance. EGFR is known to contribute to antiestrogen resistance: we further show that HIF2α drives hypoxic induction of EGFR and that EGFR induces HIF2α expression. Downregulation or inhibition of EGFR led to decreased HIF2α levels. This positive and bilateral HIF2-EGFR regulatory crosstalk promotes antiestrogen resistance and, where intrinsic hypoxic resistance exists, therapy itself may exacerbate the problem. Finally, inhibition of HIFs by FM19G11 restores antiestrogen sensitivity in resistant cells. Targeting HIF2 may be useful for counteracting antiestrogen resistance in the clinic.},
  author       = {Alam, Muhammad Wasi and Persson, Camilla and Reinbothe, Susann and Kazi, Julhash U. and Rönnstrand, Lars and Wigerup, Caroline and Ditzel, Henrik J and Lykkesfeldt, Anne E and Påhlman, Sven and Jögi, Annika},
  issn         = {1949-2553},
  language     = {eng},
  number       = {10},
  pages        = {50--11238},
  publisher    = {Impact Journals, LLC},
  series       = {Oncotarget},
  title        = {HIF2α contributes to antiestrogen resistance via positive bilateral crosstalk with EGFR in breast cancer cells.},
  url          = {http://dx.doi.org/10.18632/oncotarget.7167},
  volume       = {7},
  year         = {2016},
}