Summary Androgen receptor (AR) signaling is a key driver of prostate cancer (PC). While androgen-deprivation therapy is transiently effective in advanced disease, tumors often progress to a lethal castration-resistant state (CRPC). We show that recurrent PC-driver mutations in SPOP stabilize the TRIM24 protein, which promotes proliferation under low androgen conditions. TRIM24 augments AR signaling, and AR and TRIM24 co-activated genes are significantly up-regulated in CRPC. Expression of TRIM24 protein increases from primary PC to CRPC, and both TRIM24 protein levels and the AR/TRIM24 gene signature predict disease-recurrence. Analyses in CRPC cells reveal that the TRIM24 bromodomain and the AR-interacting motif are essential to support proliferation. These data provide a rationale for therapeutic TRIM24 targeting in SPOP-mutant and CRPC patients.
Highlights d ARfl and ARv7 genomic binding is interdependent and colocalized d ARv7, unlike ARfl, preferentially represses transcription d Expression of ARv7-repressed genes negatively correlates with recurrence d Re-expression of ARv7-repressed genes may serve as a biomarker of ARv7 inhibition
Mutations in estrogen receptor alpha (ER) that confer resistance to existing classes of endocrine therapies are detected in up to 30% of patients who have relapsed during endocrine treatments. Since a significant proportion of therapy-resistant breast cancer metastases continue to be dependent on ER signaling, there remains a critical need to develop the next generation of ER antagonists that can overcome aberrant ER activity. Through our drug discovery efforts, we identified H3B-5942 which covalently inactivates both wild-type and mutant ER by targeting Cys530 and enforcing a unique antagonist conformation. H3B-5942 belongs to a class of ER antagonist referred to as Selective Estrogen Receptor Covalent Antagonists (SERCAs).In vitro comparisons of H3B-5942 with standard of care (SoC) 10, 2018; DOI: 10.1158/2159-8290.CD-17-1229 3Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on July SignificanceNearly 30% of endocrine-therapy resistant breast cancer metastases harbor constitutively activating mutations in ER. Selective Estrogen Receptor Covalent Antagonist (SERCA) H3B-5942 engages C530 of both ER WT and ER MUT, promotes a unique antagonist conformation, and demonstrates improved in vitro and in vivo activity over standard of care (SoC) agents.Importantly, single agent efficacy can be further enhanced by combining with CDK4/6 or mTOR inhibitors.
Treatment-induced mutations in the ligand-binding domain of the androgen receptor (AR) are known to change antagonists into agonists. Recently, the F877L mutation has been described to convert enzalutamide into an agonist. This mutation was seen to co-occur in the endogenous AR allele of LNCaP cells, next to the T878A mutation. Here, we studied the effects of enzalutamide on the F877L and T878A mutants, as well as the double-mutant AR (F877L/T878A). Molecular modeling revealed favorable structural changes in the double-mutant AR that lead to a decrease in steric clashes for enzalutamide. Ligand-binding assays confirmed that the F877L mutation leads to an increase in relative binding affinity for enzalutamide, but only the combination with the T878A mutation resulted in a strong agonistic activity. This correlated with changes in coregulator recruitment and chromatin interactions. Our data show that enzalutamide is only a very weak partial agonist of the AR F877L, and a strong partial agonist of the double-mutant AR.
BackgroundTo date, all studies conducted on breast cancer diagnosis have focused on the expression of the full-length 66-kDa estrogen receptor alpha (ERα66). However, much less attention has been paid to a shorter 46-kDa isoform (ERα46), devoid of the N-terminal region containing the transactivation function AF-1. Here, we investigated the expression levels of ERα46 in breast tumors in relation to tumor grade and size, and examined the mechanism of its generation and its specificities of coregulatory binding and its functional activities.MethodsUsing approaches combining immunohistochemistry, Western blotting, and proteomics, antibodies allowing ERα46 detection were identified and the expression levels of ERα46 were quantified in 116 ERα-positive human breast tumors. ERα46 expression upon cellular stress was studied, and coregulator bindings, transcriptional, and proliferative response were determined to both ERα isoforms.ResultsERα46 was expressed in over 70% of breast tumors at variable levels which sometimes were more abundant than ERα66, especially in differentiated, lower-grade, and smaller-sized tumors. We also found that ERα46 can be generated via internal ribosome entry site-mediated translation in the context of endoplasmic reticulum stress. The binding affinities of both unliganded and fully-activated receptors towards co-regulator peptides revealed that the respective potencies of ERα46 and ERα66 differ significantly, contributing to the differential transcriptional activity of target genes to 17β estradiol (E2). Finally, increasing amounts of ERα46 decrease the proliferation rate of MCF7 tumor cells in response to E2.ConclusionsWe found that, besides the full-length ERα66, the overlooked ERα46 isoform is also expressed in a majority of breast tumors. This finding highlights the importance of the choice of antibodies used for the diagnosis of breast cancer, which are able or not to detect the ERα46 isoform. In addition, since the function of both ERα isoforms differs, this work underlines the need to develop new technologies in order to discriminate ERα66 and ERα46 expression in breast cancer diagnosis which could have potential clinical relevance.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-016-0780-7) contains supplementary material, which is available to authorized users.
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