Genome-independent hypoxic repression of estrogen receptor alpha in breast cancer cells

BMC Cancer

Research Article

Adam J. Krieg¹  Mercè Padró²  Raymond J. Louie²  Brian V. Lananna²  Denise A. Chan²  Luika A. Timmerman³ 

[1] Department of Obstetrics and Gynecology, Kansas University Medical Center, 66160, Kansas City, KS, USA;Department of Radiation Oncology, University of California, 94115, San Francisco, CA, USA;Helen Diller Family Comprehensive Cancer Center, University of California, UCSF Mail stop 0875, 2340 Sutter Street, Room N361, 94115, San Francisco, CA, USA;Helen Diller Family Comprehensive Cancer Center, University of California, UCSF Mail stop 0875, 2340 Sutter Street, Room N361, 94115, San Francisco, CA, USA;

关键词: Hypoxia;    Estrogen receptor;    HIF;    HIF-1α;    HIF-1 alpha;    Endocrine therapy;    Breast cancer;    Tamoxifen;    Aromatase inhibitor;    Drug resistance;    Endocrine therapy resistance;   

DOI  :  10.1186/s12885-017-3140-9

 received in 2015-09-11, accepted in 2017-02-15,  发布年份 2017

来源: Springer

【 摘 要 】

BackgroundAbout 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.MethodsUsing 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.ResultsWe 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.ConclusionsThese 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.

【 授权许可】

CC BY   
© The Author(s). 2017