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Approximately 40% of patients with oestrogen receptor (ER)-positive breast cancers do not respond to endocrine therapies; furthermore, most responsive tumours eventually become resistant. We have identified a novel oestrogen-responsive Hsp90 co-chaperone and immunophilin, FKBPL, which affects the stability and signalling of ER with implications for breast cancer growth and sensitivity to endocrine therapies. MCF7 cells stably overexpressing FKBPL demonstrate a slower rate of proliferation and become highly dependent on oestrogen for their growth. This dependence on oestrogen renders these cells dramatically more sensitive to tamoxifen and fulvestrant. FKBPL overexpressing cells also exhibit decreased levels of ER and an oestrogen-responsive gene, cathepsin D, critical for breast cancer growth, survival and invasion. Moreover, knockdown of FKBPL using a targeted siRNA approach dramatically increases both ER and cathepsin D protein levels and cell resistance to tamoxifen. FKBPL has been previously implicated in the stabilisation of the cyclin-dependent kinase inhibitor, p21 . Loss of p21 has been associated with a tamoxifen growth-inducing phenotype and hyperphosphorylation of ER at Ser118, with increased expression of ER-regulated genes. Following FKBPL knockdown, we have observed a fall in p21 levels and subsequent increase in Ser118 phosphorylation following treatment with 17β-estradiol or tamoxifen while FKBPL overexpressing cells exhibit the reverse effects. Our in vitro data support a model in which high levels of FKBPL would stabilise p21, decrease ER phosphorylation and abrogate tamoxifen-induced agonist potency, thereby increasing drug sensitivity, and suggest that FKBPL may have prognostic value that might impact upon tumour proliferative capacity and improve patient outcome. In addition, analysis of two publically available breast cancer microarray patient cohorts demonstrated that high FKBPL expression was correlated with increased overall and distant metastasis-free survival.