Title |
Genome-independent hypoxic repression of estrogen receptor alpha in breast cancer cells
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Published in |
BMC Cancer, March 2017
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DOI | 10.1186/s12885-017-3140-9 |
Pubmed ID | |
Authors |
Mercè Padró, Raymond J. Louie, Brian V. Lananna, Adam J. Krieg, Luika A. Timmerman, Denise A. Chan |
Abstract |
About 75-80% of breast tumors express the estrogen receptor alpha (ER-α) and are treated with endocrine-target therapeutics, making this the premier therapeutic modality in the breast cancer clinic. However, acquired resistance is common and about 20% of resistant tumors loose ER-α expression via unknown mechanisms. Inhibition of ER-α loss could improve endocrine therapeutic efficacy, benefiting a significant number of patients. Here we test whether tumor hypoxia might commonly produce ER-α loss. Using standard molecular and cellular biological assays and a work station/incubator with controllable oxygen levels, we analyze the effects of hypoxia on ER-α protein, mRNA, and transcriptional activity in a panel of independently-derived ER-α positive cell lines. These lines were chosen to represent the diverse genetic backgrounds and mutations commonly present in ER-α positive tumors. Using shRNA-mediated knockdown and overexpression studies we also elucidate the role of hypoxia-inducible factor 1-alpha (HIF-1α) in the hypoxia-induced decrease in ER-α abundance. We present the first comprehensive overview of the effects of bona fide low environmental oxygen (hypoxia) and HIF-1α activity on ER-α abundance and transcriptional activity. We find that stabilized HIF-1α induces rapid loss of ER-α protein in all members of our diverse panel of breast cancer cell lines, which involves proteolysis rather than transcriptional repression. Reduced ER-α severely attenuates ER-α directed transcription, and inhibits cell proliferation without overt signs of cell death in the cell lines tested, despite their varying genomic backgrounds. These studies reveal a common hypoxia response that produces reduced ER-α expression and cell cycle stalling, and demonstrate a common role for HIF-1α in ER-α loss. We hypothesize that inhibitors of HIF-1α or the proteasome might stabilize ER-α expression in breast tumors in vivo, and work in combination with endocrine therapies to reduce resistance. Our data also suggests that disease re-occurrence in patients with ER-α positive tumors may arise from tumor cells chronically resident in hypoxic environments. We hypothesize that these non-proliferating cells may survive undetected until conditions change to oxygenate the environment, or cells eventually switch to proliferation via other signaling pathways. |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
Unknown | 34 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Student > Ph. D. Student | 12 | 35% |
Student > Bachelor | 5 | 15% |
Researcher | 4 | 12% |
Student > Master | 3 | 9% |
Student > Doctoral Student | 2 | 6% |
Other | 3 | 9% |
Unknown | 5 | 15% |
Readers by discipline | Count | As % |
---|---|---|
Biochemistry, Genetics and Molecular Biology | 6 | 18% |
Medicine and Dentistry | 6 | 18% |
Pharmacology, Toxicology and Pharmaceutical Science | 2 | 6% |
Neuroscience | 2 | 6% |
Immunology and Microbiology | 2 | 6% |
Other | 11 | 32% |
Unknown | 5 | 15% |