Minireview: Alternative Activation Pathways for the Androgen Receptor in Prostate Cancer

May combine two claims.

Preventing direct ligand binding inhibits AR-driven gene expression and cell proliferation, but transactivation of the receptor by other factors renders these treatments ineffective in CR disease.

“The prevention of direct ligand binding inhibits AR-driven gene expression and cell proliferation, but transactivation of the receptor by other factors renders these treatments ineffective in CR disease.”

May combine two claims.

The levels of IL-6 and its soluble receptor IL-6sR in circulating plasma are increased in patients with aggressive metastatic disease and can be predictive of recurrence after treatment of localized cancer.

“The levels of IL-6 and its soluble receptor, IL-6sR, in circulating plasma is increased in patients with aggressive metastatic disease and can be predictive of recurrence after treatment of localized cancer (17).”

• cites [17] Shariat, 2001, Plasma levels of interleukin-6 and its soluble receptor are associated with prostate cancer progression and metastasis., Urology sourceNot checked yet

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IL-6 treatment is agonistic for AR activity in LAPC-4 cells expressing wild-type AR and in MDA-PCa-2b cells expressing double-mutant AR (L701H and T877A), whereas IL-6 inhibits ligand-independent AR activity in T877A AR-expressing LNCaP cells.

“The effect of IL-6 treatment on LAPC-4 cells, which express a wild-type AR and in MDA-PCa-2b cells, which express a double-mutant AR (substitutions at L701H and T877A) is agonistic, whereas IL-6 inhibits ligand-independent AR activity in T877A ARexpressing LNCaP cells (20).”

• cites [20] Malinowska, 2009, Interleukin-6 stimulation of growth of prostate cancer in vitro and in vivo through activation of the androgen receptor., Endocr Relat Cancer sourceNot checked yet

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Extracellular peptide signals in the form of growth factors and cytokines can promote AR activity, although not through the same ligand-binding mechanism as DHT.

“Extracellular peptide signals, in the form of growth factors and cytokines, can promote AR activity, although not through the same ligand-binding mechanism as DHT.”

May combine two claims.

IL-6 predominantly stimulates Janus kinase signaling and activation of STAT proteins, especially STAT3; MAPK and phosphatidylinositol-3 kinase activation can also occur depending on context.

“The predominant effect of IL-6 in many cell types is the stimulation of Janus kinase (JAK) signaling and activation of signal transducers and activators of transcription (STAT) proteins, especially STAT3; however, activation of MAPK and phosphatidylinositol-3 kinase (PI3K) can also occur depending on the context (13)(14)(15).”

• cites [13] Blaszczyk, 2004, Osteoblast-derived factors induce androgen-independent proliferation and expression of prostate-specific antigen in human prostate cancer cells., Clin Cancer Res sourceNot checked yet

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• cites [14] Culig, 2006, Androgen axis in prostate cancer., J Cell Biochem sourceNot checked yet

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• cites [15] Culig, 2005, Interleukin-6 regulation of prostate cancer cell growth., J Cell Biochem sourceNot checked yet

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May combine two claims.

Castration-resistant (CR) prostate tumor cells continue to grow after hormonal therapy that markedly reduces testosterone and dihydrotestosterone, but they still require AR expression and activity.

“Despite CR tumor cells being able to continue to grow after hormonal therapy in which testosterone and dihydrotestosterone are markedly reduced, they still require the expression and activity of the AR.”

• cites [5] Debes, 2002, The role of androgens and the androgen receptor in prostate cancer., Cancer Lett sourceNot checked yet

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Chronic stimulation of LNCaP cells with IL-6 results in stimulation of AR via STAT signaling, inducing PSA expression even in the absence of androgen.

“In contrast, chronic stimulation of LNCaP cells with IL-6 results in stimulation of AR via STAT signaling, thus inducing PSA expression, even in the absence of androgen (22).”

• cites [22] Debes, 2005, p300 regulates androgen receptor-independent expression of prostate-specific antigen in prostate cancer cells treated chronically with interleukin-6., Cancer Res sourceNot checked yet

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STAT3 interacts directly with amino acids 234-558 of the AR, and this interaction is dependent upon phosphorylation of STAT3 at Ser-722.

“STAT3 interacts directly with amino acids 234 -558 of the AR (23), an interaction that is dependent upon phosphorylation of STAT3 at Ser-722 (24).”

• cites [23] Ueda, 2002, Activation of the androgen receptor N-terminal domain by interleukin-6 via MAPK and STAT3 signal transduction pathways., J Biol Chem sourceNot checked yet

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• cites [24] Aaronson, 2007, An androgen-IL-6-Stat3 autocrine loop re-routes EGF signal in prostate cancer cells., Mol Cell Endocrinol sourceNot checked yet

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May combine two claims.

AR transactivation in CR prostate cancer can occur through non-mutually-exclusive mechanisms including increased receptor expression, receptor mutations, altered coregulatory proteins, cross talk with signaling pathways, and constitutively active splice variants.

“This transactivation of the AR can occur through a number of non-mutually-exclusive mechanisms, including increased expression of the receptor; generation of mutations in the receptor, which can change its canonical regulation; and altered action of coregulatory proteins, through cross talk with other signaling pathways or through the action of constitutively active splice variants.”

May combine two claims.

The androgen receptor (AR) is a nuclear hormone receptor transcription factor that mediates androgen effects on target tissues and plays a central role in prostate cancer development and progression.

“The androgen receptor (AR), which is a member of the nuclear hormone receptor superfamily of proteins, is the transcription factor that is responsible for mediating the effects of androgens upon target tissues, and it has been demonstrated to play a central role in the development and progression of prostate cancer.”

• cites [4] Lamont, 2010, Androgen regulation of gene expression., Adv Cancer Res sourceNot checked yet

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Loss of the regulatory phosphatase activity of PTEN results in unchecked PI3K activity, which generates the secondary messenger PIP3 from PIP2.

“Loss of the regulatory phosphatase activity by PTEN results in unchecked PI3K activity (initiated by a number of transmembrane receptors), which generates the secondary messenger phospholipid phosphatidylinositol 3,5-triphosphate (PIP3) from phosphatidylinositol 4,5-diphosphate (PIP2).”

May combine two claims.

Overexpression of GRP is sufficient to confer LNCaP xenograft tumor growth in castrated mice, in accordance with the observed AR transactivation.

“Overexpression of GRP is also sufficient to confer LNCaP xenograft tumor growth in castrated mice, in accordance with the observed AR transactivation (40).”

• cites [40] Yang, 2009, Aberrant activation of androgen receptor in a new neuropeptide- autocrine model of androgen-insensitive prostate cancer., Cancer Res sourceNot checked yet

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Treatment of ectopic AR-expressing DU-145 cells with EGF in the absence of androgen induces an androgen-responsive luciferase promoter to a similar extent as androgen treatment, an effect inhibited by the AR antagonist bicalutamide.

“In one study, treatment of ectopic AR-expressing DU-145 cells (CR prostate cancer cells isolated from a brain me-tastasis that do not express an endogenous AR) with EGF in the absence of androgen induces an androgen-responsive luciferase promoter to a similar extent as with androgen treatment, an effect that is inhibited by the AR antagonist bicalutamide (35).”

• cites [35] Culig, 1994, Androgen receptor activation in prostatic tumor cell lines by insulin-like growth factor-I, keratinocyte growth factor, and epidermal growth factor., Cancer ResNot checked yet

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Ack1 promotes cell survival in part by targeting the tumor suppressor Wwox for degradation and activating AKT.

“A downstream mediator of a number of receptor tyrosine kinases, Ack1 promotes cell survival in part by targeting the tumor suppressor Wwox for degradation and activating AKT (58).”

• cites [58] Mahajan, 2010, Shepherding AKT and androgen receptor by Ack1 tyrosine kinase., J Cell Physiol sourceNot checked yet

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Constitutive NF-κB activity maintains high levels of the AR in the nucleus, which promotes constant transcription of proliferative genes.

“Thus, constitutive NF-B activity maintains high levels of the AR in the nucleus, which promotes constant transcription of proliferative genes.”

May combine two claims.

Treatment of LNCaP and LAPC-4 cells with bombesin/gastrin-releasing peptide (GRP) in the absence of androgen induces AR phosphorylation at Tyr-534 via Src activation and induces subsequent AR-mediated transcription.

“Treatment of LNCaP and LAPC-4 cells with GRP in the absence of androgen induces AR phosphorylation at Tyr-534, via Src activation, and induces subsequent AR-mediated transcription (28).”

• cites [28] Liu, 2010, Dasatinib inhibits site-specific tyrosine phosphorylation of androgen receptor by Ack1 and Src kinases., Oncogene sourceNot checked yet

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When prostate cancer cells are treated with forskolin, AR-driven transcription is increased from AR-responsive promoters, an effect quenched by the addition of AR antagonists bicalutamide and flutamide.

“When prostate cancer cells are treated with the inhibitor forskolin (a naturally derived molecule that activates adenylyl cyclase, thus increasing the intracellular levels of cAMP and consequently protein kinase A), AR-driven transcription is increased from ARresponsive promoters, an effect that is quenched by the addition of AR antagonists bicalutamide and flutamide (55,56).”

• cites [55] Nazareth, 1996, Activation of the human androgen receptor through a protein kinase A signaling pathway., J Biol Chem sourceNot checked yet

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• cites [56] Sadar, 1999, Androgen-independent induction of prostate-specific antigen gene expression via cross-talk between the androgen receptor and protein kinase A signal transduction pathways., J Biol Chem sourceNot checked yet

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May combine two claims.

PIP3 presence in the cell membrane recruits the pleckstrin homology domains of signaling kinases including Akt/protein kinase B, and recruitment of Akt by PIP3 leads to a conformational change that allows activation by transfer of a phosphate moiety by phosphoinositide-dependent kinase 1 and 2.

“PIP3 presence in the cell membrane recruits the pleckstrin homology domains of a number of signaling kinases, including Akt/protein kinase B. Recruitment of Akt by PIP3 leads to conformational change that allows activation to occur by the transfer of a phosphate moiety by the constitutively active phosphoinositide-dependent kinase 1 and 2.”

May combine two claims.

LNCaP xenografts that overexpress ectopic Ack1 demonstrate significantly increased growth in castrated mice, which is inhibited by the kinase inhibitor dasatinib.

“LNCaP xenografts that overexpress ectopic Ack1 demonstrate significantly increased growth in castrated mice, which is inhibited by the kinase inhibitor dasatinib (28).”

• cites [28] Liu, 2010, Dasatinib inhibits site-specific tyrosine phosphorylation of androgen receptor by Ack1 and Src kinases., Oncogene sourceNot checked yet

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May combine two claims.

Vav3 signaling induces nuclear localization of the AR via activation of Rho guanosine triphosphatase Rac1, whose downstream signaling includes members of the MAPK pathway, including ERK.

“This signaling pathway induces nuclear localization of the AR via the activation Rho guanosine triphosphatase Rac1, whose downstream signaling includes members of the MAPK pathway, including ERK (46).”

• cites [46] Lyons, 2008, Ligand-independent activation of androgen receptors by Rho GTPase signaling in prostate cancer., Mol Endocrinol sourceNot checked yet

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PTEN is one of the most frequently mutated and/or deleted tumor suppressors in human cancers, and its expression is often lost or reduced in advanced metastatic tumors compared with primary prostate tumors.

“PTEN is one of the most frequently mutated and/or deleted tumor suppressors in human cancers, and its expression is often lost or reduced in advanced metastatic tumors compared with primary prostate tumors (48).”

• cites [48] Suzuki, 1998, Interfocal heterogeneity of PTEN/MMAC1 gene alterations in multiple metastatic prostate cancer tissues., Cancer ResNot checked yet

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At least part of NF-κB/p52 transactivation of the AR is due to NF-κB direct interaction with the NH2 domain of the AR, which allows for recruitment of coactivators like p300 and augmented binding to the promoter regions of AR-targeted genes.

“The exact mechanism for this is not clearly understood; however, it appears that at least part of the transactivation is due to NF-B direct interaction with the NH 2 domain of the AR, which allows for recruitment of coactivators like p300 and augmented binding to the promoter regions of AR-targeted genes (54).”

• cites [54] Nadiminty, 2010, Aberrant activation of the androgen receptor by NF-κB2/p52 in prostate cancer cells., Cancer Res sourceNot checked yet

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In addition to being a target of AR transcriptional activity in prostate epithelial cells, the IGF-I receptor can induce intracellular signaling cascades that regulate phosphorylation of the AR, thus affecting its transcriptional activation both in the presence and absence of androgen.

“In addition to being a target of AR transcriptional activity in prostate epithelial cells, IGF-I receptor can induce intracellular signaling cascades that regulate phosphorylation of the AR, thus affecting its transcriptional activation both in the presence and absence of androgen (37).”

• cites [37] Wu, 2006, Interaction of IGF signaling and the androgen receptor in prostate cancer progression., J Cell Biochem sourceNot checked yet

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Treatment of C4-2 cells with the Src inhibitor protein phosphatase 2 in androgen-free conditions results in decreased activation of mouse mammary tumor virus and PSA luciferase reporters as well as reduced recruitment of the AR to the endogenous PSA gene enhancer region.

“Treatment of C4-2 cells with the Src inhibitor protein phosphatase 2 in androgen-free conditions results in a decreased activation of mouse mammary tumor virus and PSA luciferase reporters as well as reduced recruitment of the AR to the endogenous PSA gene enhancer region (44).”

• cites [44] Asim, 2008, Src kinase potentiates androgen receptor transactivation function and invasion of androgen-independent prostate cancer C4-2 cells., Oncogene sourceNot checked yet

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The expression of Vav3, a Rho guanosine triphosphate guanine nucleotide exchange factor, is upregulated in prostate cancer and has been demonstrated to enhance EGF/IGF activation of the AR in the absence of androgen.

“The expression of Vav3, a Rho guanos-ine triphosphate guanine nucleotide exchange factor, is upregulated in prostate cancer and has been demonstrated to enhance EGF/IGF activation of the AR in the absence of androgen (46).”

• cites [46] Lyons, 2008, Ligand-independent activation of androgen receptors by Rho GTPase signaling in prostate cancer., Mol Endocrinol sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

Alterations to the activity of some kinases, especially those with oncogenic or tumor-suppressive functions, have the potential to promote malignant signaling and drive the development and progression of many kinds of cancers, including prostate cancer.

“Alterations to the activity of some kinases, especially to those with oncogenic or tumor-suppressive functions, has the potential to promote malignant signaling and drive the development and progression of many kinds of cancers, including prostate (42).”

• cites [42] Blume-Jensen, 2001, Oncogenic kinase signalling., Nature sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Activated Akt has a number of downstream effects, including survival/apoptosis evasion, proliferation, and protein synthesis/cell growth.

“Activated Akt has a number of downstream effects, including survival/apoptosis evasion, proliferation, and protein synthesis/cell growth (47).”

• cites [47] Sarker, 2009, Targeting the PI3K/AKT pathway for the treatment of prostate cancer., Clin Cancer Res sourceNot checked yet

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Silencing of FOXO1 in PTEN-positive cells increases the basal activity of the AR and can sensitize the receptor to lower levels of androgens and to IL-6.

“Interestingly, silencing of FOXO1 in PTEN-positive cells increases the basal activity of the AR and can sensitize the receptor to lower levels of androgens and by IL-6 (52).”

• cites [52] Liu, 2008, A transcription-independent function of FOXO1 in inhibition of androgen-independent activation of the androgen receptor in prostate cancer cells., Cancer Res sourceNot checked yet

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May combine two claims.

Ack1 can directly interact with the AR and specifically phosphorylate the AR at Tyr-267, a modification required for optimal AR recruitment to target genes at low-to no-androgen conditions.

“Ack1 can directly interact with the AR and can specifically phosphorylate the AR at Tyr-267, a modification that has been described to be required for optimal AR recruitment to target genes at low-to no-androgen conditions (59).”

• cites [59] Mahajan, 2007, Activated Cdc42-associated kinase Ack1 promotes prostate cancer progression via androgen receptor tyrosine phosphorylation., Proc Natl Acad Sci USA sourceNot checked yet

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The expression of EGF and its receptor EGFR is increased in patients with advanced, aggressive prostate cancer, and both molecules have been implicated in the development and progression of many other kinds of tumors.

“The expression of EGF and its receptor (EGFR) are increased in patients with advanced, aggressive prostate cancer, and both molecules have been implicated in the development and progression of many other kinds of tumors (33).”

• cites [33] Zhu, 2008, Androgen receptor and growth factor signaling cross-talk in prostate cancer cells., Endocr Relat Cancer sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

Approximately 70 different missense mutations have been described in patient samples, with varying consequences upon androgen receptor activity.

“Approximately 70 different missense mutations have been described in patient samples, with varying consequences upon AR activity.”

• cites [71] Brooke, 2009, The role of androgen receptor mutations in prostate cancer progression., Curr Genomics sourceNot checked yet

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• cites [72] Culig, 2001, Androgen receptor mutations in carcinoma of the prostate: significance for endocrine therapy., Am J Pharmacogenomics sourceNot checked yet

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May combine two claims.

Expression of androgen receptor N-terminal domain decoy molecules comprising amino acids 1-558 in LNCaP xenografts decreased tumor growth and serum PSA abundance after castration.

“Expression of AR NTD decoy molecules, comprised of an aminoterminal portion of the AR comprising amino acids 1-558 in LNCaP xenografts decreased growth of the tumor and the abundance of serum PSA after castration (69).”

• cites [69] Quayle, 2007, Androgen receptor decoy molecules block the growth of prostate cancer., Proc Natl Acad Sci USA sourceNot checked yet

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Knockdown of HDAC6 in C4-2 cells inhibits nuclear localization of endogenous androgen receptor and inhibits expression of PSA.

“Knockdown of HDAC6 in C4-2 cells inhibits the nuclear localization of endogenous AR and inhibits expression of PSA (63).”

• cites [63] Ai, 2009, HDAC6 regulates androgen receptor hypersensitivity and nuclear localization via modulating Hsp90 acetylation in castration-resistant prostate cancer., Mol Endocrinol sourceNot checked yet

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Classified as probably not a substantial claim.

The proposed mechanism suggests that N-terminal decoy molecules bind to interacting proteins that inhibit activation of endogenous androgen receptor.

“The proposed mechanism suggests that these N-terminal decoy molecules bind to interacting proteins that inhibit activation of endogenous AR; however, the specific factors retained by the decoys were not identified.”

• cites [69] Quayle, 2007, Androgen receptor decoy molecules block the growth of prostate cancer., Proc Natl Acad Sci USA sourceNot checked yet

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May combine two claims.

Three ligand-binding domain mutations commonly found in patient tumors, H874Y, T877A, and T877S, impart additional capacity for androgen receptor binding to motifs associated with coregulator proteins and stimulate expression of AR target genes, in addition to being activated by selective AR modulators, antiandrogens, and other hormones, compared with wild-type AR.

“Three LBD mutations that are commonly found in patient tumors, H874Y, T877A, and T877S, impart additional capacity for AR binding to motifs associated with coregulator proteins as well as stimulating the expression of AR target genes in addition to being activated by selective AR modulators, antiandrogens, and other hormones when compared with the wild-type AR (73).”

• cites [73] Brooke, 2008, Mechanisms of androgen receptor activation in advanced prostate cancer: differential co-activator recruitment and gene expression., Oncogene sourceNot checked yet

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May combine two claims.

Localization of AR-V7 is cytoplasmic in many benign and androgen-dependent tissues but is found in the nucleus in castration-recurrent tumors.

“Localization of AR-V7 is cytoplasmic in many benign and AD tissues but is found in the nucleus in CR tumors (78).”

• cites [78] Guo, 2009, A novel androgen receptor splice variant is up-regulated during prostate cancer progression and promotes androgen depletion-resistant growth., Cancer Res sourceNot checked yet

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SET9 methylates the androgen receptor on Lys-632, a modification that facilitates N-C interaction of the receptor and promotes recruitment to AR-regulated genes.

“SET9 is able to methylate the AR on Lys-632, a modification that facilitates N-C interaction of the receptor and promotes recruitment to AR-regulated genes.”

• cites [65] Gaughan, 2011, Regulation of the androgen receptor by SET9-mediated methylation., Nucleic Acids Research sourceNot checked yet

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When ectopically expressed in PC-3 cells, the AR-V7 variant is localized in the nuclei and is constitutively active in the absence of androgen.

“When ectopically expressed in PC-3 cells, the AR-V7 variant is localized in the nuclei and is constitutively active in the absence of androgen (75).”

• cites [75] Hu, 2009, Ligand-independent androgen receptor variants derived from splicing of cryptic exons signify hormone-refractory prostate cancer., Cancer Res sourceNot checked yet

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The N-terminal domain and DNA-binding domain have ligand-independent nuclear import ability, whereas the ligand-binding domain exhibits ligand-dependent activity.

“The NTD and DNA-binding domain (DBD) have ligand-independent nuclear import ability, whereas the LBD exhibits ligand-dependent activity (70).”

• cites [70] Kaku, 2008, Characterization of nuclear import of the domain-specific androgen receptor in association with the importin α/β and Ran-guanosine 5′-triphosphate systems., Endocrinology sourceNot checked yet

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The ability of MDV3100 to inhibit androgen receptor transcriptional activity and demonstrate clinical efficacy in a phase I/II trial suggests that ligand-directed therapeutics might still have a place in future treatment regimes.

“The ability of these molecules to inhibit AR transcriptional activity and demonstrate clinical efficacy in a phase I/II trial of patients with CR tumors, in the case of MDV 3100, suggests that ligand-directed therapeutics might still have a place in future treatment regimes.”

• cites [81] Tran, 2009, Development of a second-generation antiandrogen for treatment of advanced prostate cancer., Science sourceNot checked yet

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May combine two claims.

Human AR-V7 and mouse AR-V4 demonstrate ligand-free activation of a 4xARE-Luc promoter as well as promoting castration-recurrent LNCaP tumor growth.

“Two such variants, human AR-V7, identified in CR prostate cancer specimens, and mouse AR-V4, from the murine Myc-CaP cell line, demonstrate ligand-free activation of a 4xARE-Luc promoter as well as promoting CR LNCaP tumor growth.”

• cites [77] Watson, 2010, Constitutively active androgen receptor splice variants expressed in castration-resistant prostate cancer require full-length androgen receptor., Proc Natl Acad Sci USA sourceNot checked yet

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The WxxLF motif is located in Tau-5, and Tau-5 along with Tau-1 are necessary and sufficient for the intrinsic activity of the androgen receptor N-terminal domain and activity of the AR.

“The WxxLF motif is located in a region that was originally identified as Tau-5 (transactivation unit-5), and along with a similar region called Tau-1, it was found that these regions are necessary and sufficient for the intrinsic activity of the AR N-terminal domain (NTD) and activity of the AR (68).”

• cites [68] Callewaert, 2006, Interplay between two hormone-independent activation domains in the androgen receptor., Cancer Res sourceNot checked yet

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Approximately half of the ligand-independent transcriptional activity of the androgen receptor in castration-recurrent prostate cancer cells is conferred by the amino-terminal WxxLF domain, which can interact with the AR ligand-binding domain.

“Approximately half of the ligandindependent transcriptional activity of the AR in CR prostate cancer cells is conferred by the amino-terminal WxxLF domain, which can interact with the AR LBD.”

• cites [67] Dehm, 2007, Selective role of an NH2-terminal WxxLF motif for aberrant androgen receptor activation in androgen depletion-independent prostate cancer cells., Cancer Res sourceNot checked yet

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Two additional nuclear localization signals exist in the N-terminal domain and ligand-binding domain with distinct import pathways: the DBD NLS is Ran and importin alpha/beta dependent, whereas the NTD and LBD NLS are Ran dependent but importin alpha/beta independent.

“Two additional NLS exist in the NTD in LBD with distinct pathways for import: the NLS of the DBD is Ran and importin ␣/␤ dependent, whereas the NLS of the NTD and LBD are Ran dependent but importin ␣/␤ independent (70).”

• cites [70] Kaku, 2008, Characterization of nuclear import of the domain-specific androgen receptor in association with the importin α/β and Ran-guanosine 5′-triphosphate systems., Endocrinology sourceNot checked yet

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May combine two claims.

MDV3100 binds to the ligand-binding domain of the androgen receptor, similarly to bicalutamide.

“EPI-001 targets the NTD of the AR (80), whereas MDV 3100 binds to the LBD (81), similarly to bicalutamide.”

• cites [81] Tran, 2009, Development of a second-generation antiandrogen for treatment of advanced prostate cancer., Science sourceNot checked yet

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May combine two claims.

Activating mutations of the androgen receptor can create a promiscuous receptor, alter interactions with coregulatory proteins, and impair intramolecular N-C interactions.

“Activating mutations of the AR have the capacity to create a promiscuous receptor, alter interactions with coregulatory proteins, and impair intramolecular N-C interactions (71).”

• cites [71] Brooke, 2009, The role of androgen receptor mutations in prostate cancer progression., Curr Genomics sourceNot checked yet

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May combine two claims.

Movement of the androgen receptor into the nucleus is largely dependent upon the nuclear localization signal present in the hinge region of the receptor, with a portion of that regulation also found within the N-terminal domain.

“The movement of the AR into the nucleus is largely dependent upon the nuclear localization signal (NLS) present in the hinge region of the receptor; however, a portion of that regulation is also found within the NTD.”

• cites [70] Kaku, 2008, Characterization of nuclear import of the domain-specific androgen receptor in association with the importin α/β and Ran-guanosine 5′-triphosphate systems., Endocrinology sourceNot checked yet

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May combine two claims.

The activity of AR-V7 and AR-V4 variants still depends on the presence of full-length androgen receptor, although treatment with MDV3100 or siRNA knockdown of full-length AR inhibited transcription and androgen-free growth.

“The activity of these variants still depends on the presence of a full-length AR, although treatment with the AR antagonist MDV3100 or siRNA knockdown of full-length AR inhibited transcription and androgen-free growth (77).”

• cites [77] Watson, 2010, Constitutively active androgen receptor splice variants expressed in castration-resistant prostate cancer require full-length androgen receptor., Proc Natl Acad Sci USA sourceNot checked yet

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May combine two claims.

Activating signals for the androgen receptor in castration-recurrent disease arise from several non-mutually-exclusive mechanisms including extracellular peptide signals such as EGF and IL-6, upregulation of intracellular kinase pathways such as PI3K/Akt and MAPK activation, altered activity of coregulatory proteins, and intrinsic activation of the AR itself through deregulated intramolecularinter

“Activating signals arise from several, non-mutually-exclusive mechanisms including 1) extracellular peptide signals such as EGF and IL-6, 2) upregulation of intracellular kinase pathways, such as PI3K/Akt and MAPK activation, 3) altered activity of coregulatory proteins, and 4) intrinsic activation of the AR itself through deregulated intramolecular interaction or through expression of constitutiv”

Probably not a substantial claim: may not pass S4 (based). May combine two claims.

A new generation of androgen receptor antagonists are reported to be stronger and more durable inhibitors of transcriptional activity than current compounds used in the clinic.

“A new generation of AR antagonists holds much clinical promise because they are reported to be stronger and more durable inhibitors of transcriptional activity than current compounds used in the clinic.”