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Hypoxia and Hypoxia-Inducible Factors in Normal and Malignant Breast Epithelium

Helczynska, Karolina LU (2008) In Lund University Faculty of Medicine Doctoral Dissertation Series 2008:61.
Abstract
Breast cancer treatment is based on tumor and patient related factors such as tumor stage, grade, hormonal status, HER2 status, patient age, and family history to name a few. It is today widely acknowledged that hypoxia and hypoxia-inducible factors (HIF:s) contribute to tumor progression. We therefore set out to explore the impact of hypoxia on mammary epithelial differentiation and what consequences the hypoxic response might have on breast cancer development and behavior. We found that hypoxia induces

a less differentiated, estrogen receptor (ER)-negative/cytokeratin (CK) 19-positive phenotype in mammary cancer cells in vivo and in vitro and suggest that hypoxiainduced dedifferentiation is one of the mechanisms behind... (More)
Breast cancer treatment is based on tumor and patient related factors such as tumor stage, grade, hormonal status, HER2 status, patient age, and family history to name a few. It is today widely acknowledged that hypoxia and hypoxia-inducible factors (HIF:s) contribute to tumor progression. We therefore set out to explore the impact of hypoxia on mammary epithelial differentiation and what consequences the hypoxic response might have on breast cancer development and behavior. We found that hypoxia induces

a less differentiated, estrogen receptor (ER)-negative/cytokeratin (CK) 19-positive phenotype in mammary cancer cells in vivo and in vitro and suggest that hypoxiainduced dedifferentiation is one of the mechanisms behind hypoxia-driven malignant progression. Hypoxia was also found to significantly impair both morphological and functional differentiation of non-transformed, immortalized epithelial mammary cells grown in three-dimensional cultures. Heterogeneous ER expression in breast cancer was

additionally found to be related to cyclin D1, a cell cycle regulator frequently overexpressed in breast cancer. As cyclin D1 expression was not affected by hypoxia, our findings suggest two separate mechanisms behind varied ER expression in breast cancer. The two pivotal regulators of hypoxic response, HIF-1α and HIF-2α, were analyzed in two cohorts of breast cancer patients and found to be un-correlated suggesting HIF-α

subtype specific mechanisms of induction. Furthermore, HIF-2α was found to be an independent prognostic factor related to distant recurrence. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • Professor Enblad, Gunilla, Dept. of Oncology, Radiology and Clinical Immunology, Uppsala University
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Differentiation, Hypoxia, Breast cancer, Breast, HiF-1, HiF-2, 3D-cultures, prognosis
in
Lund University Faculty of Medicine Doctoral Dissertation Series
volume
2008:61
pages
111 pages
publisher
Department of Laboratory Medicine, Lund University
defense location
Main Lecture Hall, Dept. of Pathology, University Hospital MAS
defense date
2008-05-29 09:15
ISSN
1652-8220
ISBN
978-91-86059-14-9
language
English
LU publication?
yes
id
d74d8c94-d194-43c5-806c-1200ae730aff (old id 1149298)
date added to LUP
2008-05-09 11:05:19
date last changed
2016-09-19 08:44:46
@phdthesis{d74d8c94-d194-43c5-806c-1200ae730aff,
  abstract     = {Breast cancer treatment is based on tumor and patient related factors such as tumor stage, grade, hormonal status, HER2 status, patient age, and family history to name a few. It is today widely acknowledged that hypoxia and hypoxia-inducible factors (HIF:s) contribute to tumor progression. We therefore set out to explore the impact of hypoxia on mammary epithelial differentiation and what consequences the hypoxic response might have on breast cancer development and behavior. We found that hypoxia induces<br/><br>
a less differentiated, estrogen receptor (ER)-negative/cytokeratin (CK) 19-positive phenotype in mammary cancer cells in vivo and in vitro and suggest that hypoxiainduced dedifferentiation is one of the mechanisms behind hypoxia-driven malignant progression. Hypoxia was also found to significantly impair both morphological and functional differentiation of non-transformed, immortalized epithelial mammary cells grown in three-dimensional cultures. Heterogeneous ER expression in breast cancer was<br/><br>
additionally found to be related to cyclin D1, a cell cycle regulator frequently overexpressed in breast cancer. As cyclin D1 expression was not affected by hypoxia, our findings suggest two separate mechanisms behind varied ER expression in breast cancer. The two pivotal regulators of hypoxic response, HIF-1α and HIF-2α, were analyzed in two cohorts of breast cancer patients and found to be un-correlated suggesting HIF-α<br/><br>
subtype specific mechanisms of induction. Furthermore, HIF-2α was found to be an independent prognostic factor related to distant recurrence.},
  author       = {Helczynska, Karolina},
  isbn         = {978-91-86059-14-9},
  issn         = {1652-8220},
  keyword      = {Differentiation,Hypoxia,Breast cancer,Breast,HiF-1,HiF-2,3D-cultures,prognosis},
  language     = {eng},
  pages        = {111},
  publisher    = {Department of Laboratory Medicine, Lund University},
  school       = {Lund University},
  series       = {Lund University Faculty of Medicine Doctoral Dissertation Series},
  title        = {Hypoxia and Hypoxia-Inducible Factors in Normal and Malignant Breast Epithelium},
  volume       = {2008:61},
  year         = {2008},
}