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The androgen receptor (AR) is a member of the steroid-hormone family that is involved in the regulation of normal growth and development within a wide range of target organs. It is a member of the family of steroid receptors that includes progesterone, glucocorticoid, and mineralocorticoid receptors. It links a transcription factor that controls specific genes involved in different, sometimes opposite, cellular processes: it can stimulate or suppress cell proliferation and apoptosis, relying on the concurrent signaling pathways activated. AR transcription is age- and cell-type-dependent, which is regulated by the presence of circulating androgens.
Androgen receptor consists of 4 domains, a DNA-binding domain, an N-terminal domain, a hinge, and a ligand-binding domain, and functions as a nuclear transcription factor. In the absence of ligand, AR attaches to heat shock proteins and is located mainly in the cytoplasm. In the presence of ligand, the ligand-binding domain is unbound from heat shock protein and AR translocates into the nucleus, where the DNA-binding domain binds to androgen-responsive elements in DNA and recruits additional corepressors, coactivators, and transcriptional modulators.
However, AR can also be activated by a non-transcriptional/non-genomic mechanism that does not need RNA or DNA interaction and that modulates AR activity by signal transduction in an ERK-dependent or -independent manner. ERK-mediated AR signaling involves cytoplasmic AR which interacts with phosphoinositide 3-kinase (PI3K), Ras GTPase and Src proteins. Non ERK-mediated AR signaling may involve the mammalian target of rapamycin (mTOR) phosphorylation, the forkhead box protein O1 (FOXO1) inactivation, and the protein kinase A (PKA) activation and leads to increased cell proliferation.
Figure 1. Androgen receptor activation. (Gerratana L, et al., 2018)
There are an increasing number of researches relating the action of the AR to breast, liver, larynx, and testicular cancers. Prostate cancer cells, similar to normal prostate cells, require androgens to grow and survive. The growth of prostate cancer depends on the ratio of the rate of cell proliferation to the rate of cell death. In prostate cancer, the rate of proliferation is higher than that of death, leading to continuous net growth. Androgens and the AR are the main regulators of this ratio. In many cases, the initiation of prostate cancer can be attributed to the activation of distinct growth-promoting pathways. One prominent example is the androgen-dependent upregulation of members of the E-twenty-six (ETS) family of transcription factors by gene fusions between the AR-regulated TMPRSS2 gene promoter and the coding region of the ETS family members erythroblast transformation-specific (ERG) and ETS variant 1 (ETV1), which have been estimated to occur in about 50% of prostate tumors. Other signaling pathways shown to be involved in prostate cancer occurrence and progression include the PI3K and RAS/RAF pathways; dysregulation of these pathways in both early and late stage prostate cancer was implicated by genomic profiling. Androgen signaling has been the primary target for the treatment of prostate cancer. Many novel therapies are in development to overcome the mechanisms that always create resistance to the currently available AR antagonists and strategies for androgen deprivation.
AR is expressed in about 80 and 60 % of primary and metastatic breast tumors, respectively. Its expression varies across the clinical subtypes, approximately 84-95 % in Estrogen Receptor (ER)+ tumors, 50-63 % in ER-/HER2+ tumors, and 10-53 % in triple negative breast cancer (TNBC). The signaling effect of AR may be different across breast cancer subtypes, and particularly important is its interaction with ER signaling. When estrogen is low, testosterone is preferentially converted to estradiol, an ER ligand, instead of to 5α-dihydrotestosterone (DHT), an AR ligand, therefore translating androgen supply into ER-driven tumorigenesis. Consequently, a higher tumor AR-to-ER ratio is independently associated with lymph node metastasis and poor survival. When the AR-to-ER ratio is low, or when estrogens are available, androgen metabolism will activate AR to compete for EREs. In this case, AR can be antitumorigenic. Thus, understanding the differential AR signaling effects would enable us to harness the clinical availability of new potent AR-antagonists to potentially improve current endocrine therapies for ER+ breast cancers.
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