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PMID: 20010940 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

Hypoxia potentiates Notch signaling in breast cancer leading to decreased E-cadherin expression and increased cell migration and invasion.

British journal of cancer ·Vol. 102 ·No. 2 ·2010-01-19 ·Pages 351-60

Chen J, Imanaka N, Chen J, Griffin JD

Abstract

Epithelial-to-mesenchymal transition (EMT) is associated with decreased adhesion and acquisition of metastatic potential of breast cancer cells. Epithelial-to-mesenchymal transition is mediated, in part, by two transcription repressors, Snail and Slug, that are known to be targets of the Notch signaling pathway, and JAGGED1-induced Notch activation increases EMT. However, the events that lead to increased Notch activity during EMT of breast cancer cells are unknown. The accumulation of hypoxia inducible factors (HIFs) under hypoxia was detected by western blot analysis, and their effects on Notch signaling were measured by an in vitro Notch reporter assay. The expression of Notch target genes under hypoxia was tested by real-time PCR. The knockdown of HIF-1alpha was mediated by retroviral delivery of shRNA. The expression of Slug and Snail under hypoxia was measured by real-time PCR. Breast cancer cell migration and invasion under hypoxia were tested with cell migration and invasion kits. Hypoxia increased the expression of Notch target genes such as HES1 and HEY1 in breast cancer cells, as was expression of Notch receptors and ligands. The mechanism is likely to involve the accumulation of HIF-1alpha and HIF-2alpha in these cells by hypoxia, which synergised with the Notch co-activator MAML1 in potentiating Notch activity. Hypoxia inducible factor-1alpha was found to bind to HES1 promoter under hypoxia. Knockdown of HIF-1alpha with shRNA inhibited both HES1 and HEY1 expression under hypoxia. Hypoxia increased the expression of Slug and Snail, and decreased the expression of E-cadherin, hallmarks of EMT. Notch pathway inhibition abrogated the hypoxia-mediated increase in Slug and Snail expression, as well as decreased breast cancer cell migration and invasion. Hypoxia-mediated Notch signaling may have an important role in the initiation of EMT and subsequent potential for breast cancer metastasis.

MeSH Terms
Basic Helix-Loop-Helix Transcription Factors/biosynthesis Breast Neoplasms/metabolism,physiopathology Cadherins/biosynthesis Cell Cycle Proteins/biosynthesis Cell Movement/physiology Female Homeodomain Proteins/biosynthesis Humans Hypoxia/physiopathology Neoplasm Invasiveness/physiopathology Receptors, Notch/biosynthesis Signal Transduction Transcription Factor HES-1
Chemicals
Basic Helix-Loop-Helix Transcription Factors Cadherins Cell Cycle Proteins HEY1 protein, human Homeodomain Proteins Receptors, Notch Transcription Factor HES-1 HES1 protein, human
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Chen J
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Imanaka N
Chen J
Griffin J D
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Article Info
Journal
British journal of cancer
Abbr.
Br J Cancer
ISSN
1532-1827
DOI
10.1038/sj.bjc.6605486
Published
2010-01-19
Epub
2009-00-15
Pages
351-60
Language
English
Region
England
NLM ID
0370635
PMCID
PMC2816657
Subset
IM
Grants
NCI NIH HHS · R01 CA036167 · United States
NCI NIH HHS · R37 CA036167 · United States
NCI NIH HHS · CA-36167 · United States
External Links
PubMed source DOI: 10.1038/sj.bjc.6605486 PMC Full Text View journal details
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