To validate this hypothesis, we compared AR variants in metastases obtained by rapid autopsy of patients treated with flutamide or bicalutamide, or by excision of lymph node metastases from hormone-naïve patients.
Recent findings unmasked the importance of androgen receptor (AR) signaling in regulation of DNA repair, and alterations of the AR-DNA repair factor axis were shown to promote aggressive phenotypes including metastasis.
Single-stranded conformational polymorphism and sequencing analyses revealed AR missense mutations in 29% (4/14) of the primary tumors and in one (14%) metastasis.
These areas include continued emphasis on the androgen receptor in the androgen-independent state, parallel growth pathways such as AKT and HER2 that may act in conjunction or independently of the androgen receptor, the supporting environment that allows for the development of metastatic disease, and standard cytotoxic targets, such as the microtubule.
Mutation profiling in mice provides direct evidence that somatic AR variants are selected by therapy, a finding validated in human metastases from distinct treatment groups.
Lesions affecting tumour suppressor genes usually occur as single events, whereas mutations in genes involved in androgen receptor signalling commonly involve multiple, convergent events in different metastases.
In this context, androgen receptor (AR) is the Achilles' heel, being critically important and various mechanisms ranging from receptor mutations to secondary signaling pathways are responsible for some of the biological heterogeneity, demanding a multimodal approach.
These results demonstrate that a shorter CAG repeat sequence in the androgen receptor gene predicts higher grade and advanced stage of prostate cancer at diagnosis, and metastasis and mortality from the disease.
We report the detection of 2 different mutant ARs within the same metastatic tumour sample harvested in a patient with advanced PCa who had escaped androgen deprivation.
Together, our results demonstrate that AR can promote melanoma metastasis via altering the miRNA-539-3p/USP13/MITF/AXL signal and targeting this newly identified signal with AR degradation enhancer ASC-J9 may help us to better suppress the melanoma metastasis.
The phase III ARAMIS study shows that the androgen-receptor antagonist darolutamide delays metastasis in men with castration-resistant prostate cancer by a median of 22 months compared with a placebo.
A second tumor-suppressive lncRNA PCAT29, located 20 kb downstream of DRAIC, is regulated identically by AR and FOXA1 and also suppresses cellular migration and metastasis.
This chapter discusses the mechanisms driving the therapeutic resistance of taxanes and antiandrogen therapies in CRPC, and the role of AR in potential interventions toward overcoming such resistance in patients with advanced metastatic disease.
Overexpression of oncogenic lncRNAs promotes tumor-cell proliferation and metastasis through chromatin looping and distal engagement with the androgen receptor, antisense gene regulation, alternative splicing, and impeding DNA repair.
Androgen receptor (AR) signaling is a critical survival pathway for prostate cancer cells, and androgen-deprivation therapy (ADT) remains the principal treatment for patients with locally advanced and metastatic disease.