FKBPL regulates estrogen receptor signaling and determines response to endocrine therapy.
The HSP90 chaperone and immunophilin FKBPL is an estrogen-responsive gene that interacts with estogen receptor alpha (ERalpha) and regulates its levels. In this study, we explored the effects of FKBPL on breast cancer proliferation. Breast cancer cells stably overexpressing FKBPL became dependent on estrogen for their growth and were dramatically more sensitive to the antiestrogens tamoxifen and fulvestrant, whereas FKBPL knockdown reverses this phenotype. FKBPL knockdown also decreased the levels of the cell cycle inhibitor p21WAF1 and increased ERalpha phosphorylation on Ser(118) in response to 17beta-estradiol and tamoxifen. In support of the likelihood that these effects explained FKBPL-mediated cell growth inhibition and sensitivity to endocrine therapies, FKBPL expression was correlated with increased overall survival and distant metastasis-free survival in breast cancer patients. Our findings suggest that FKBPL may have prognostic value based on its impact on tumor proliferative capacity and sensitivity to endocrine therapies, which improve outcome.
McKeen
Hayley D
HD
School of Pharmacy, McClay Research Centre and Centre for Cancer Research and Cell Biology, Queen's University, Belfast, Northern Ireland BT9 7BL, United Kingdom.
Byrne
Christopher
C
Jithesh
Puthen V
PV
Donley
Christopher
C
Valentine
Andrea
A
Yakkundi
Anita
A
O'Rourke
Martin
M
Swanton
Charles
C
McCarthy
Helen O
HO
Hirst
David G
DG
Robson
Tracy
T
D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002402:Cathepsin D / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D004967:Estrogens / Q000494:pharmacology; D000077267:Fulvestrant; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D020104:Immunophilins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D047468:Immunoprecipitation; D053208:Kaplan-Meier Estimate; D015201:Meta-Analysis as Topic; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding; D034622:RNA Interference; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D022021:Tacrolimus Binding Proteins; D013629:Tamoxifen / Q000494:pharmacology*; D014162:Transfection
D018931:Antineoplastic Agents, Hormonal; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D047628:Estrogen Receptor alpha; D004967:Estrogens; C400101:FKBPL protein, human; D018841:HSP90 Heat-Shock Proteins; D013629:Tamoxifen; D000077267:Fulvestrant; D012694:Serine; D004958:Estradiol; D002402:Cathepsin D; D022021:Tacrolimus Binding Proteins; D020104:Immunophilins