Journal article
The Oncogene HER2/neu (ERBB2) Requires the Hypoxia-inducible Factor HIF-1 for Mammary Tumor Growth and Anoikis Resistance
The Journal of biological chemistry, v 288(22), pp 15865-15877
31 May 2013
PMID: 23585570
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Background:
Oncogene HER2 (ERBB2) regulates breast cancer growth and anoikis resistance.
Results:
ERBB2 requires hypoxia-inducible factor (HIF)-1 for breast cancer growth
in vivo
and anoikis resistance
in vitro
.
Conclusion:
HIF-1 plays a critical role in ERBB2-positive breast cancers.
Significance:
Genes co-regulated by ERBB2 and HIF-1 may be novel therapeutic targets for treating breast cancer.
ERBB2, a receptor tyrosine kinase amplified in breast cancer, is a well established regulator of tumor growth
in vivo
and anoikis resistance leading to disruption of architecture in three-dimensional mammary epithelial acinar structures
in vitro
. ERBB2 promotes anoikis resistance by maintaining signaling pathways and by rescuing metabolic defects and thus inhibiting accumulation of deleterious reactive oxygen species. Recent evidence suggests that hypoxia, via hypoxia-inducible factors (HIFs), can inhibit anoikis; thus, we hypothesized that HIF-1 may play a role in ERBB2-mediated anoikis resistance and oncogenesis. Indeed, tumors isolated from MMTV-Neu mice contain elevated HIF-1α levels and tumor cells created from MMTV-Neu mice harboring deletion of
Hif1
α alleles reduced primary tumor growth
in vivo
. ERBB2 overexpressing cancer cells stabilize HIF under normoxic conditions and require HIF-1 for ERBB2-mediated anchorage-independence, three-dimensional culture growth and anoikis resistance. HIF-1 reduction in ERBB2 cells was associated with induction of the pro-anoikis protein BIM and decreased ERK and AKT signaling during cell detachment. ERBB2-mediated inhibition of metabolic defects, including decreased reactive oxygen species generation in suspension, required HIF-1 expression that was critical for ERBB2-mediated oncogenesis. Gene expression profiling of hypoxic three-dimensional acinar structures identified a number of genes elevated in response to hypoxia that are known ERBB2 targets, suggesting that hypoxic conditions and ERBB2 overexpression share both phenotypic and genetic components via HIF-1 regulation. Thus, our data demonstrate that ERBB2 requires HIF-1 for tumor growth and suggest that HIF is a major downstream regulator of ERBB2 that protects cells from anoikis and metabolic stress caused by decreased matrix adhesion.
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Details
- Title
- The Oncogene HER2/neu (ERBB2) Requires the Hypoxia-inducible Factor HIF-1 for Mammary Tumor Growth and Anoikis Resistance
- Creators
- Kelly A Whelan - From the Departments ofLuciana P Schwab - theSergey V Karakashev - From the Departments ofLisa Franchetti - Pathology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102 andGregg J Johannes - Pathology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102 andTiffany N Seagroves - theMauricio J Reginato - From the Departments of
- Publication Details
- The Journal of biological chemistry, v 288(22), pp 15865-15877
- Publisher
- American Society for Biochemistry and Molecular Biology; 9650 Rockville Pike, Bethesda, MD 20814, U.S.A
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology
- Web of Science ID
- WOS:000319822300040
- Scopus ID
- 2-s2.0-84878417516
- Other Identifier
- 991014877712904721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology