Hypoxia potentiates Notch signaling in breast cancer leading to decreased E-cadherin expression and increased cell migration and invasion
Open accessAbstract
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: Hypoxia-mediated Notch signaling may have an important role in the initiation of EMT and subsequent potential for breast cancer metastasis.
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The HIF pathway indirectly promotes EMT through Notch, TGF-β, integrin-linked kinase, certain tyrosine kinase receptors, Wnt, and Hedgehog.
“The HIF pathway also indirectly promotes EMT through a number of cell signaling pathways, including Notch (74, 75), TGF-β (76), integrin-linked kinase (77), certain tyrosine kinase receptors (48), Wnt (73), and Hedgehog (78, 79).”
From Hypoxic control of metastasis (2016) · cites this paper as [74]
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- Authors
- Chen, J., Imanaka, N., Chen, J., & Griffin, J. D.
- Affiliations
- Dana-Farber Cancer Institute (US)
- Corresponding author
- Griffin, J D
- ORCID
- Griffin, J D
- Venue
- British Journal of Cancer
- Published
- 2009-12-15
- Volume
- 102
- Issue
- 2
- Pages
- 351-360
- ISSN
- 0007-0920 (ISSN-L)
- 1532-1827
- PMC
- PMC2816657
- OpenAlex
- W2027497744
- Cited by
- 346
- References
- 40
- Citations by year
- 2026: 6 · 2025: 8 · 2024: 15 · 2023: 13 · 2022: 26 · 2021: 18 · 2020: 28 · 2019: 23 · 2018: 22 · 2017: 31 · 2016: 23 · 2015: 25 · 2014: 17 · 2013: 30 · 2012: 28
- FWCI
- 6.82
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc-sa
- www.springer.com/tdm (unspecified)
- Locations
- British Journal of Cancer (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (R01CA036167, CA36167, R37CA036167)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Keywords
- hypoxia, Notch signaling, breast cancer, epithelial-mesenchymal transition, E-cadherin, Slug, snails, HIF-1α, HIF-2α, Hes1, Hey1, MAML1, cell migration, tumor invasion, metastasis
- MeSH terms
- Transcription Factor HES-1, Hypoxia, Breast Neoplasms, Cell Movement, Female, Humans, Neoplasm Invasiveness, Signal Transduction, Cadherins, Homeodomain Proteins, Cell Cycle Proteins, Basic Helix-Loop-Helix Transcription Factors, Basic Helix-Loop-Helix Proteins, Receptors, Notch
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