In some cell types, testosterone interacts directly with androgen receptors, whereas, in others, testosterone is converted by
5-alpha-reductase to dihydrotestosterone, an even more potent
agonist for androgen receptor activation.[15] Testosterone appears to be the primary androgen receptor-activating hormone in the
Wolffian duct, whereas dihydrotestosterone is the main androgenic hormone in the
urogenital sinus,
urogenital tubercle, and
hair follicles.[16] Testosterone is therefore responsible primarily for the development of male
primary sexual characteristics, whilst dihydrotestosterone is responsible for
secondary male characteristics.
Androgens cause slow maturation of the bones, but more of the potent maturation effect comes from the
estrogen produced by
aromatization of androgens.
Steroid users of teen age may find that their growth had been stunted by androgen and/or estrogen excess. People with too little sex hormones can be short during puberty but end up taller as adults as in
androgen insensitivity syndrome or
estrogen insensitivity syndrome.[17]
Knockout-mice studies have shown that the androgen receptor is essential for normal female fertility, being required for development and full functionality of the
ovarian follicles and
ovulation, working through both intra-ovarian and
neuroendocrine mechanisms.[18]
Maintenance of male skeletal integrity
Via the androgen receptor, androgens play a key role in the maintenance of male skeletal integrity. The regulation of this integrity by androgen receptor (AR) signaling can be attributed to both
osteoblasts and
osteocytes.[19]
Role in females
The AR plays a role in regulating female sexual, somatic, and behavioral functions. Experimental data using AR
knockout female mice, provides evidence that the promotion of cardiac growth, kidney hypertrophy, cortical bone growth and regulation of
trabecular bone structure is a result of DNA-binding-dependent actions of the AR in females.
Moreover, the importance of understanding female androgen receptors lies in their role in several genetic disorders including androgen insensitivity syndrome (AIS).
Complete (CAIS) and
partial (PAIS) which are a result of
mutations in the genes that code for AR. These mutations cause the inactivation of AR due to mutations conferring resistance to circulating testosterone, with more than 400 different AR mutations reported.[citation needed]
Androgens (also called androgenic hormones), such as testosterone or dihydrotestosterone, are understood to exert their primary effects through binding to an androgen receptor in the cytosol. The receptor is translocated to the nucleus upon androgen binding and ultimately results in the transcriptional regulation of a number of genes via androgen responsive elements.[20] This androgen response mechanism is perhaps best known and characterized in the context of male sexual differentiation and puberty, but plays a role in a variety of tissue types and processes.[21][22] Upon binding to androgens, the androgen receptor dissociates from accessory proteins, translocates into the nucleus, dimerizes, and then stimulates transcription of androgen-responsive genes.[23]
The binding of an androgen to the androgen receptor results in a
conformational change in the receptor that, in turn, causes dissociation of
heat shock proteins, transport from the
cytosol into the
cell nucleus, and
dimerization. The androgen receptor dimer binds to a specific sequence of DNA known as a
hormone response element, where it forms macromolacular protein condensates that might facilitate rapid gene regulation as consequence of local high protein concentrations together with other coregulators.[24] Androgen receptors interact with other proteins in the nucleus, resulting in up- or down-regulation of specific
gene transcription.[25] Up-regulation or activation of transcription results in increased synthesis of
messenger RNA, which, in turn, is translated by
ribosomes to produce specific proteins. One of the known target genes of androgen receptor activation is the
insulin-like growth factor 1 receptor (IGF-1R).[26] Thus, changes in levels of specific proteins in cells is one way that androgen receptors control cell behavior.
One function of androgen receptor that is independent of direct binding to its target DNA sequence is facilitated by recruitment via other
DNA-binding proteins. One example is
serum response factor, a protein that activates several genes that cause muscle growth.[27]
More recently, androgen receptors have been shown to have a second mode of action. As has been also found for other
steroid hormone receptors such as
estrogen receptors, androgen receptors can have actions that are independent of their interactions with DNA.[14][35] Androgen receptors interact with certain
signal transduction proteins in the cytoplasm. Androgen binding to cytoplasmic androgen receptors can cause rapid changes in cell function independent of changes in gene transcription, such as changes in
ion transport. Regulation of signal transduction pathways by cytoplasmic androgen receptors can indirectly lead to changes in gene transcription, for example, by leading to phosphorylation of other transcription factors.
Genetics
Gene
In humans, the androgen receptor is encoded by the ARgene located on the
X chromosome at Xq11–12.[36][37]
The AR gene contains
CAG repeats that affect receptor function, where fewer repeats leads to increased receptor sensitivity to circulating androgens and more repeats leads to decreased receptor sensitivity. Studies have shown that racial variation in CAG repeats exists,[43][44] with African-Americans having fewer repeats than non-Hispanic white Americans.[43] The racial trends in CAG repeats parallels the incidence and mortality of prostate cancer in these two groups.
Mutations
The
enhancer and the gene encoding for these receptors contain recurrent mutations, such as structural rearrangements and copy number changes, acquired in the progression of metastatic castration-resistant prostate cancer (mCRPC) treatment with therapy targeting these receptors (abiraterone,
enzalutamide), make the disease progression determined by the androgen receptor genotype.[45]
Structure
Isoforms
Two
isoforms of the androgen receptor (A and B) have been identified:[46]
Like other nuclear receptors, the androgen receptor is modular in structure and is composed of the following functional
domains labeled A through F:[48]
activation function 1 (AF-1) between residues 101 and 370 required for full
ligand-activated transcriptional activity
activation function 5 (AF-5) between residues 360–485 is responsible for the
constitutive activity (activity without bound ligand)
dimerization surface involving residues 1–36 (containing the FXXLF motif; where F =
phenylalanine, L =
leucine, and X = any amino acid residue) and 370–494, both of which interact with the ligand binding domain (LBD) in an intramolecular[50][51][52] head-to-tail interaction[53][54][55]
Alteration of ARs may lead to treatment resistance (castration resistance) in prostate cancer as there may be
missense mutations of the
ligand binding domain, amplifications of the gene coding for this receptor or in its enhancer, mostly, suggesting the presence of different subclones with different genotypes of these receptors.[45]
Interactions
Androgen receptor has been shown to
interact with:
^Bardin CW, Brown T, Isomaa VV, Jänne OA (1983). "Progestins can mimic, inhibit and potentiate the actions of androgens". Pharmacology & Therapeutics. 23 (3): 443–59.
doi:
10.1016/0163-7258(83)90023-2.
PMID6371845.
^Frank GR (September 2003). "Role of estrogen and androgen in pubertal skeletal physiology". Medical and Pediatric Oncology. 41 (3): 217–21.
doi:
10.1002/mpo.10340.
PMID12868122.
^Gelmann EP (July 2002). "Molecular biology of the androgen receptor". Journal of Clinical Oncology. 20 (13): 3001–3015.
doi:
10.1200/JCO.2002.10.018.
PMID12089231.
^Trapman J, Klaassen P, Kuiper GG, van der Korput JA, Faber PW, van Rooij HC, Geurts van Kessel A, Voorhorst MM, Mulder E, Brinkmann AO (May 1988). "Cloning, structure and expression of a cDNA encoding the human androgen receptor". Biochemical and Biophysical Research Communications. 153 (1): 241–8.
doi:
10.1016/S0006-291X(88)81214-2.
PMID3377788.
^Kennedy WR, Alter M, Sung JH (July 1968). "Progressive proximal spinal and bulbar muscular atrophy of late onset. A sex-linked recessive trait". Neurology. 18 (7): 671–80.
doi:
10.1212/WNL.18.7.671.
PMID4233749.
S2CID45735233.
^
abSartor O, Zheng Q, Eastham JA (February 1999). "Androgen receptor gene CAG repeat length varies in a race-specific fashion in men without prostate cancer". Urology. 53 (2): 378–80.
doi:
10.1016/s0090-4295(98)00481-6.
PMID9933058.
^Brinkmann AO, Klaasen P, Kuiper GG, van der Korput JA, Bolt J, de Boer W, Smit A, Faber PW, van Rooij HC, Geurts van Kessel A (1989). "Structure and function of the androgen receptor". Urological Research. 17 (2): 87–93.
doi:
10.1007/BF00262026.
PMID2734982.
S2CID19706366.
^Ayub M, Levell MJ (August 1989). "The effect of ketoconazole related imidazole drugs and antiandrogens on [3H] R 1881 binding to the prostatic androgen receptor and [3H]5 alpha-dihydrotestosterone and [3H]cortisol binding to plasma proteins". J. Steroid Biochem. 33 (2): 251–5.
doi:
10.1016/0022-4731(89)90301-4.
PMID2788775.
^Park JJ, Irvine RA, Buchanan G, Koh SS, Park JM, Tilley WD, Stallcup MR, Press MF, Coetzee GA (November 2000). "Breast cancer susceptibility gene 1 (BRCAI) is a coactivator of the androgen receptor". Cancer Research. 60 (21): 5946–9.
PMID11085509.
^Beauchemin AM, Gottlieb B, Beitel LK, Elhaji YA, Pinsky L, Trifiro MA (2001). "Cytochrome c oxidase subunit Vb interacts with human androgen receptor: a potential mechanism for neurotoxicity in spinobulbar muscular atrophy". Brain Research Bulletin. 56 (3–4): 285–97.
doi:
10.1016/S0361-9230(01)00583-4.
PMID11719263.
S2CID24740136.
^
abcIshitani K, Yoshida T, Kitagawa H, Ohta H, Nozawa S, Kato S (July 2003). "p54nrb acts as a transcriptional coactivator for activation function 1 of the human androgen receptor". Biochemical and Biophysical Research Communications. 306 (3): 660–5.
doi:
10.1016/S0006-291X(03)01021-0.
PMID12810069.
^Niki T, Takahashi-Niki K, Taira T, Iguchi-Ariga SM, Ariga H (February 2003). "DJBP: a novel DJ-1-binding protein, negatively regulates the androgen receptor by recruiting histone deacetylase complex, and DJ-1 antagonizes this inhibition by abrogation of this complex". Molecular Cancer Research. 1 (4): 247–61.
PMID12612053.
^Bonaccorsi L, Muratori M, Carloni V, Marchiani S, Formigli L, Forti G, Baldi E (August 2004). "The androgen receptor associates with the epidermal growth factor receptor in androgen-sensitive prostate cancer cells". Steroids. 69 (8–9): 549–52.
doi:
10.1016/j.steroids.2004.05.011.
hdl:2158/395763.
PMID15288768.
S2CID23831527.
^Nishimura K, Ting HJ, Harada Y, Tokizane T, Nonomura N, Kang HY, Chang HC, Yeh S, Miyamoto H, Shin M, Aozasa K, Okuyama A, Chang C (August 2003). "Modulation of androgen receptor transactivation by gelsolin: a newly identified androgen receptor coregulator". Cancer Research. 63 (16): 4888–94.
PMID12941811.
^Veldscholte J, Berrevoets CA, Brinkmann AO, Grootegoed JA, Mulder E (March 1992). "Anti-androgens and the mutated androgen receptor of LNCaP cells: differential effects on binding affinity, heat-shock protein interaction, and transcription activation". Biochemistry. 31 (8): 2393–9.
doi:
10.1021/bi00123a026.
PMID1540595.
^Nemoto T, Ohara-Nemoto Y, Ota M (September 1992). "Association of the 90-kDa heat shock protein does not affect the ligand-binding ability of androgen receptor". The Journal of Steroid Biochemistry and Molecular Biology. 42 (8): 803–12.
doi:
10.1016/0960-0760(92)90088-Z.
PMID1525041.
S2CID24978960.
^Hayes SA, Zarnegar M, Sharma M, Yang F, Peehl DM, ten Dijke P, Sun Z (March 2001). "SMAD3 represses androgen receptor-mediated transcription". Cancer Research. 61 (5): 2112–8.
PMID11280774.
^Gobinet J, Auzou G, Nicolas JC, Sultan C, Jalaguier S (December 2001). "Characterization of the interaction between androgen receptor and a new transcriptional inhibitor, SHP". Biochemistry. 40 (50): 15369–77.
doi:
10.1021/bi011384o.
PMID11735420.
^Matsuda T, Junicho A, Yamamoto T, Kishi H, Korkmaz K, Saatcioglu F, Fuse H, Muraguchi A (April 2001). "Cross-talk between signal transducer and activator of transcription 3 and androgen receptor signaling in prostate carcinoma cells". Biochemical and Biophysical Research Communications. 283 (1): 179–87.
doi:
10.1006/bbrc.2001.4758.
PMID11322786.
^Mu X, Chang C (October 2003). "TR2 orphan receptor functions as negative modulator for androgen receptor in prostate cancer cells PC-3". The Prostate. 57 (2): 129–33.
doi:
10.1002/pros.10282.
PMID12949936.
S2CID24134119.
In some cell types, testosterone interacts directly with androgen receptors, whereas, in others, testosterone is converted by
5-alpha-reductase to dihydrotestosterone, an even more potent
agonist for androgen receptor activation.[15] Testosterone appears to be the primary androgen receptor-activating hormone in the
Wolffian duct, whereas dihydrotestosterone is the main androgenic hormone in the
urogenital sinus,
urogenital tubercle, and
hair follicles.[16] Testosterone is therefore responsible primarily for the development of male
primary sexual characteristics, whilst dihydrotestosterone is responsible for
secondary male characteristics.
Androgens cause slow maturation of the bones, but more of the potent maturation effect comes from the
estrogen produced by
aromatization of androgens.
Steroid users of teen age may find that their growth had been stunted by androgen and/or estrogen excess. People with too little sex hormones can be short during puberty but end up taller as adults as in
androgen insensitivity syndrome or
estrogen insensitivity syndrome.[17]
Knockout-mice studies have shown that the androgen receptor is essential for normal female fertility, being required for development and full functionality of the
ovarian follicles and
ovulation, working through both intra-ovarian and
neuroendocrine mechanisms.[18]
Maintenance of male skeletal integrity
Via the androgen receptor, androgens play a key role in the maintenance of male skeletal integrity. The regulation of this integrity by androgen receptor (AR) signaling can be attributed to both
osteoblasts and
osteocytes.[19]
Role in females
The AR plays a role in regulating female sexual, somatic, and behavioral functions. Experimental data using AR
knockout female mice, provides evidence that the promotion of cardiac growth, kidney hypertrophy, cortical bone growth and regulation of
trabecular bone structure is a result of DNA-binding-dependent actions of the AR in females.
Moreover, the importance of understanding female androgen receptors lies in their role in several genetic disorders including androgen insensitivity syndrome (AIS).
Complete (CAIS) and
partial (PAIS) which are a result of
mutations in the genes that code for AR. These mutations cause the inactivation of AR due to mutations conferring resistance to circulating testosterone, with more than 400 different AR mutations reported.[citation needed]
Androgens (also called androgenic hormones), such as testosterone or dihydrotestosterone, are understood to exert their primary effects through binding to an androgen receptor in the cytosol. The receptor is translocated to the nucleus upon androgen binding and ultimately results in the transcriptional regulation of a number of genes via androgen responsive elements.[20] This androgen response mechanism is perhaps best known and characterized in the context of male sexual differentiation and puberty, but plays a role in a variety of tissue types and processes.[21][22] Upon binding to androgens, the androgen receptor dissociates from accessory proteins, translocates into the nucleus, dimerizes, and then stimulates transcription of androgen-responsive genes.[23]
The binding of an androgen to the androgen receptor results in a
conformational change in the receptor that, in turn, causes dissociation of
heat shock proteins, transport from the
cytosol into the
cell nucleus, and
dimerization. The androgen receptor dimer binds to a specific sequence of DNA known as a
hormone response element, where it forms macromolacular protein condensates that might facilitate rapid gene regulation as consequence of local high protein concentrations together with other coregulators.[24] Androgen receptors interact with other proteins in the nucleus, resulting in up- or down-regulation of specific
gene transcription.[25] Up-regulation or activation of transcription results in increased synthesis of
messenger RNA, which, in turn, is translated by
ribosomes to produce specific proteins. One of the known target genes of androgen receptor activation is the
insulin-like growth factor 1 receptor (IGF-1R).[26] Thus, changes in levels of specific proteins in cells is one way that androgen receptors control cell behavior.
One function of androgen receptor that is independent of direct binding to its target DNA sequence is facilitated by recruitment via other
DNA-binding proteins. One example is
serum response factor, a protein that activates several genes that cause muscle growth.[27]
More recently, androgen receptors have been shown to have a second mode of action. As has been also found for other
steroid hormone receptors such as
estrogen receptors, androgen receptors can have actions that are independent of their interactions with DNA.[14][35] Androgen receptors interact with certain
signal transduction proteins in the cytoplasm. Androgen binding to cytoplasmic androgen receptors can cause rapid changes in cell function independent of changes in gene transcription, such as changes in
ion transport. Regulation of signal transduction pathways by cytoplasmic androgen receptors can indirectly lead to changes in gene transcription, for example, by leading to phosphorylation of other transcription factors.
Genetics
Gene
In humans, the androgen receptor is encoded by the ARgene located on the
X chromosome at Xq11–12.[36][37]
The AR gene contains
CAG repeats that affect receptor function, where fewer repeats leads to increased receptor sensitivity to circulating androgens and more repeats leads to decreased receptor sensitivity. Studies have shown that racial variation in CAG repeats exists,[43][44] with African-Americans having fewer repeats than non-Hispanic white Americans.[43] The racial trends in CAG repeats parallels the incidence and mortality of prostate cancer in these two groups.
Mutations
The
enhancer and the gene encoding for these receptors contain recurrent mutations, such as structural rearrangements and copy number changes, acquired in the progression of metastatic castration-resistant prostate cancer (mCRPC) treatment with therapy targeting these receptors (abiraterone,
enzalutamide), make the disease progression determined by the androgen receptor genotype.[45]
Structure
Isoforms
Two
isoforms of the androgen receptor (A and B) have been identified:[46]
Like other nuclear receptors, the androgen receptor is modular in structure and is composed of the following functional
domains labeled A through F:[48]
activation function 1 (AF-1) between residues 101 and 370 required for full
ligand-activated transcriptional activity
activation function 5 (AF-5) between residues 360–485 is responsible for the
constitutive activity (activity without bound ligand)
dimerization surface involving residues 1–36 (containing the FXXLF motif; where F =
phenylalanine, L =
leucine, and X = any amino acid residue) and 370–494, both of which interact with the ligand binding domain (LBD) in an intramolecular[50][51][52] head-to-tail interaction[53][54][55]
Alteration of ARs may lead to treatment resistance (castration resistance) in prostate cancer as there may be
missense mutations of the
ligand binding domain, amplifications of the gene coding for this receptor or in its enhancer, mostly, suggesting the presence of different subclones with different genotypes of these receptors.[45]
Interactions
Androgen receptor has been shown to
interact with:
^Bardin CW, Brown T, Isomaa VV, Jänne OA (1983). "Progestins can mimic, inhibit and potentiate the actions of androgens". Pharmacology & Therapeutics. 23 (3): 443–59.
doi:
10.1016/0163-7258(83)90023-2.
PMID6371845.
^Frank GR (September 2003). "Role of estrogen and androgen in pubertal skeletal physiology". Medical and Pediatric Oncology. 41 (3): 217–21.
doi:
10.1002/mpo.10340.
PMID12868122.
^Gelmann EP (July 2002). "Molecular biology of the androgen receptor". Journal of Clinical Oncology. 20 (13): 3001–3015.
doi:
10.1200/JCO.2002.10.018.
PMID12089231.
^Trapman J, Klaassen P, Kuiper GG, van der Korput JA, Faber PW, van Rooij HC, Geurts van Kessel A, Voorhorst MM, Mulder E, Brinkmann AO (May 1988). "Cloning, structure and expression of a cDNA encoding the human androgen receptor". Biochemical and Biophysical Research Communications. 153 (1): 241–8.
doi:
10.1016/S0006-291X(88)81214-2.
PMID3377788.
^Kennedy WR, Alter M, Sung JH (July 1968). "Progressive proximal spinal and bulbar muscular atrophy of late onset. A sex-linked recessive trait". Neurology. 18 (7): 671–80.
doi:
10.1212/WNL.18.7.671.
PMID4233749.
S2CID45735233.
^
abSartor O, Zheng Q, Eastham JA (February 1999). "Androgen receptor gene CAG repeat length varies in a race-specific fashion in men without prostate cancer". Urology. 53 (2): 378–80.
doi:
10.1016/s0090-4295(98)00481-6.
PMID9933058.
^Brinkmann AO, Klaasen P, Kuiper GG, van der Korput JA, Bolt J, de Boer W, Smit A, Faber PW, van Rooij HC, Geurts van Kessel A (1989). "Structure and function of the androgen receptor". Urological Research. 17 (2): 87–93.
doi:
10.1007/BF00262026.
PMID2734982.
S2CID19706366.
^Ayub M, Levell MJ (August 1989). "The effect of ketoconazole related imidazole drugs and antiandrogens on [3H] R 1881 binding to the prostatic androgen receptor and [3H]5 alpha-dihydrotestosterone and [3H]cortisol binding to plasma proteins". J. Steroid Biochem. 33 (2): 251–5.
doi:
10.1016/0022-4731(89)90301-4.
PMID2788775.
^Park JJ, Irvine RA, Buchanan G, Koh SS, Park JM, Tilley WD, Stallcup MR, Press MF, Coetzee GA (November 2000). "Breast cancer susceptibility gene 1 (BRCAI) is a coactivator of the androgen receptor". Cancer Research. 60 (21): 5946–9.
PMID11085509.
^Beauchemin AM, Gottlieb B, Beitel LK, Elhaji YA, Pinsky L, Trifiro MA (2001). "Cytochrome c oxidase subunit Vb interacts with human androgen receptor: a potential mechanism for neurotoxicity in spinobulbar muscular atrophy". Brain Research Bulletin. 56 (3–4): 285–97.
doi:
10.1016/S0361-9230(01)00583-4.
PMID11719263.
S2CID24740136.
^
abcIshitani K, Yoshida T, Kitagawa H, Ohta H, Nozawa S, Kato S (July 2003). "p54nrb acts as a transcriptional coactivator for activation function 1 of the human androgen receptor". Biochemical and Biophysical Research Communications. 306 (3): 660–5.
doi:
10.1016/S0006-291X(03)01021-0.
PMID12810069.
^Niki T, Takahashi-Niki K, Taira T, Iguchi-Ariga SM, Ariga H (February 2003). "DJBP: a novel DJ-1-binding protein, negatively regulates the androgen receptor by recruiting histone deacetylase complex, and DJ-1 antagonizes this inhibition by abrogation of this complex". Molecular Cancer Research. 1 (4): 247–61.
PMID12612053.
^Bonaccorsi L, Muratori M, Carloni V, Marchiani S, Formigli L, Forti G, Baldi E (August 2004). "The androgen receptor associates with the epidermal growth factor receptor in androgen-sensitive prostate cancer cells". Steroids. 69 (8–9): 549–52.
doi:
10.1016/j.steroids.2004.05.011.
hdl:2158/395763.
PMID15288768.
S2CID23831527.
^Nishimura K, Ting HJ, Harada Y, Tokizane T, Nonomura N, Kang HY, Chang HC, Yeh S, Miyamoto H, Shin M, Aozasa K, Okuyama A, Chang C (August 2003). "Modulation of androgen receptor transactivation by gelsolin: a newly identified androgen receptor coregulator". Cancer Research. 63 (16): 4888–94.
PMID12941811.
^Veldscholte J, Berrevoets CA, Brinkmann AO, Grootegoed JA, Mulder E (March 1992). "Anti-androgens and the mutated androgen receptor of LNCaP cells: differential effects on binding affinity, heat-shock protein interaction, and transcription activation". Biochemistry. 31 (8): 2393–9.
doi:
10.1021/bi00123a026.
PMID1540595.
^Nemoto T, Ohara-Nemoto Y, Ota M (September 1992). "Association of the 90-kDa heat shock protein does not affect the ligand-binding ability of androgen receptor". The Journal of Steroid Biochemistry and Molecular Biology. 42 (8): 803–12.
doi:
10.1016/0960-0760(92)90088-Z.
PMID1525041.
S2CID24978960.
^Hayes SA, Zarnegar M, Sharma M, Yang F, Peehl DM, ten Dijke P, Sun Z (March 2001). "SMAD3 represses androgen receptor-mediated transcription". Cancer Research. 61 (5): 2112–8.
PMID11280774.
^Gobinet J, Auzou G, Nicolas JC, Sultan C, Jalaguier S (December 2001). "Characterization of the interaction between androgen receptor and a new transcriptional inhibitor, SHP". Biochemistry. 40 (50): 15369–77.
doi:
10.1021/bi011384o.
PMID11735420.
^Matsuda T, Junicho A, Yamamoto T, Kishi H, Korkmaz K, Saatcioglu F, Fuse H, Muraguchi A (April 2001). "Cross-talk between signal transducer and activator of transcription 3 and androgen receptor signaling in prostate carcinoma cells". Biochemical and Biophysical Research Communications. 283 (1): 179–87.
doi:
10.1006/bbrc.2001.4758.
PMID11322786.
^Mu X, Chang C (October 2003). "TR2 orphan receptor functions as negative modulator for androgen receptor in prostate cancer cells PC-3". The Prostate. 57 (2): 129–33.
doi:
10.1002/pros.10282.
PMID12949936.
S2CID24134119.