XB-ART-46074
Mol Cell Endocrinol
2013 Jan 05;3651:95-107. doi: 10.1016/j.mce.2012.10.002.
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FoxA1 corrupts the antiandrogenic effect of bicalutamide but only weakly attenuates the effect of MDV3100 (Enzalutamide™).
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Prostate cancer growth depends on androgens. Synthetic antiandrogens are used in the cancer treatment. However, antiandrogens, such as bicalutamide (BIC), have a mixed agonist/antagonist activity. Here we compare the antiandrogenic capacity of BIC to a new antiandrogen, MDV3100 (MDV) or Enzalutamide™. By reconstitution of a hormone-regulated enhancer in Xenopus oocytes we show that both antagonists trigger the androgen receptor (AR) translocation to the nucleus, albeit with a reduced efficiency for MDV. Once in the nucleus, both AR-antagonist complexes can bind sequence specifically to DNA in vivo. The forkhead box transcription factor A (FoxA1) is a negative prognostic indicator for prostate cancer disease. FoxA1 expression presets the enhancer chromatin and makes the DNA more accessible for AR binding. In this context the BIC-AR antiandrogenic effect is seriously compromised as demonstrated by a significant chromatin remodeling and induction of a robust MMTV transcription whereas the MDV-AR complex displays a more persistent antagonistic character.
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Species referenced: Xenopus laevis
Genes referenced: foxa1