Advanced

Hypoxia-inducible factor-2alpha correlates to distant recurrence and poor outcome in invasive breast cancer.

Helczynska, Karolina LU ; Larsson, Anna-Maria LU ; Holmquist Mengelbier, Linda LU ; Bridges Baxter, Esther LU ; Fredlund, Erik LU ; Borgquist, Signe LU ; Landberg, Göran LU ; Påhlman, Sven LU and Jirström, Karin LU (2008) In Cancer Research 68(22). p.9212-9220
Abstract
Differential regulation as well as target gene specificity of the two hypoxia-inducible factor (HIF)-alpha subunits HIF-1alpha and HIF-2alpha in various tumors and cell lines have been suggested. In breast cancer, the prognostic significance of HIF-1alpha is not clear-cut and that of HIF-2alpha is largely unknown. Using IHC analyses of HIF-1alpha, HIF-2alpha, and vascular endothelial growth factor (VEGF) expression in a tissue microarray of invasive breast cancer specimens from 512 patients, we investigated the expression patterns of the 2 HIF-alpha subunits in relation to established clinicopathologic variables, VEGF expression, and survival. HIF-1alpha and HIF-2alpha protein levels and their effect on survival were additionally analyzed... (More)
Differential regulation as well as target gene specificity of the two hypoxia-inducible factor (HIF)-alpha subunits HIF-1alpha and HIF-2alpha in various tumors and cell lines have been suggested. In breast cancer, the prognostic significance of HIF-1alpha is not clear-cut and that of HIF-2alpha is largely unknown. Using IHC analyses of HIF-1alpha, HIF-2alpha, and vascular endothelial growth factor (VEGF) expression in a tissue microarray of invasive breast cancer specimens from 512 patients, we investigated the expression patterns of the 2 HIF-alpha subunits in relation to established clinicopathologic variables, VEGF expression, and survival. HIF-1alpha and HIF-2alpha protein levels and their effect on survival were additionally analyzed in a second cohort of 179 patients. To evaluate the individual role of each subunit in the hypoxic response and induction of VEGF, HIF-alpha protein and HIF-alpha and VEGF mRNA levels were further studied in cultured breast cancer cells after hypoxic induction and/or knockdown of HIF-alpha subunits by siRNA by Western blot and Quantitative Real-Time PCR techniques. We showed that although HIF-1alpha and HIF-2alpha protein levels in breast cancer specimens were not interrelated, high levels of both HIF-1alpha and HIF-2alpha associated to high VEGF expression. HIF-2alpha expression was an independent prognostic factor associated to reduced recurrence-free and breast cancer-specific survival, whereas HIF-1alpha did not exhibit these correlations. In cultured cells, acute hypoxia induced both HIF-proteins. At prolonged hypoxia, HIF-2alpha remained accumulated, whereas HIF-1alpha protein levels decreased, in agreement with the oxygen level and time-dependent induction of HIFs recently reported in neuroblastoma. (Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Cancer Research
volume
68
issue
22
pages
9212 - 9220
publisher
American Association for Cancer Research Inc.
external identifiers
  • wos:000261136600016
  • pmid:19010893
  • scopus:56449095636
ISSN
1538-7445
DOI
10.1158/0008-5472.CAN-08-1135
project
CREATE Health
language
English
LU publication?
yes
id
9c788ac0-2b96-4196-9c41-9ba11d8475e7 (old id 1271428)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/19010893?dopt=Abstract
date added to LUP
2008-12-04 15:56:32
date last changed
2017-10-01 04:01:42
@article{9c788ac0-2b96-4196-9c41-9ba11d8475e7,
  abstract     = {Differential regulation as well as target gene specificity of the two hypoxia-inducible factor (HIF)-alpha subunits HIF-1alpha and HIF-2alpha in various tumors and cell lines have been suggested. In breast cancer, the prognostic significance of HIF-1alpha is not clear-cut and that of HIF-2alpha is largely unknown. Using IHC analyses of HIF-1alpha, HIF-2alpha, and vascular endothelial growth factor (VEGF) expression in a tissue microarray of invasive breast cancer specimens from 512 patients, we investigated the expression patterns of the 2 HIF-alpha subunits in relation to established clinicopathologic variables, VEGF expression, and survival. HIF-1alpha and HIF-2alpha protein levels and their effect on survival were additionally analyzed in a second cohort of 179 patients. To evaluate the individual role of each subunit in the hypoxic response and induction of VEGF, HIF-alpha protein and HIF-alpha and VEGF mRNA levels were further studied in cultured breast cancer cells after hypoxic induction and/or knockdown of HIF-alpha subunits by siRNA by Western blot and Quantitative Real-Time PCR techniques. We showed that although HIF-1alpha and HIF-2alpha protein levels in breast cancer specimens were not interrelated, high levels of both HIF-1alpha and HIF-2alpha associated to high VEGF expression. HIF-2alpha expression was an independent prognostic factor associated to reduced recurrence-free and breast cancer-specific survival, whereas HIF-1alpha did not exhibit these correlations. In cultured cells, acute hypoxia induced both HIF-proteins. At prolonged hypoxia, HIF-2alpha remained accumulated, whereas HIF-1alpha protein levels decreased, in agreement with the oxygen level and time-dependent induction of HIFs recently reported in neuroblastoma.},
  author       = {Helczynska, Karolina and Larsson, Anna-Maria and Holmquist Mengelbier, Linda and Bridges Baxter, Esther and Fredlund, Erik and Borgquist, Signe and Landberg, Göran and Påhlman, Sven and Jirström, Karin},
  issn         = {1538-7445},
  language     = {eng},
  number       = {22},
  pages        = {9212--9220},
  publisher    = {American Association for Cancer Research Inc.},
  series       = {Cancer Research},
  title        = {Hypoxia-inducible factor-2alpha correlates to distant recurrence and poor outcome in invasive breast cancer.},
  url          = {http://dx.doi.org/10.1158/0008-5472.CAN-08-1135},
  volume       = {68},
  year         = {2008},
}