Clinical Review & Education

JAMA Oncology | Review

Androgen Receptor Function and Androgen

Receptor–Targeted Therapies in Breast Cancer
A Review
Miho Kono, MD; Takeo Fujii, MD, MPH; Bora Lim, MD; Meghan Sri Karuturi, MD; Debasish Tripathy, MD;
Naoto T. Ueno, MD, PhD, FACP

Supplemental content
IMPORTANCE The androgen receptor (AR) pathway is emerging as a potential therapeutic CME Quiz at
target in breast cancer. To date, AR-targeted drugs have been approved only for treatment of jamanetwork.com/learning
prostate cancer; however, AR-targeted treatment for breast cancer is an area of active and CME Questions
investigation. Through review of preclinical studies, retrospective clinical studies, and clinical page 1291
trials, we examined the biology of AR and AR-related pathways, the potential for AR-targeted
therapies in breast cancer, and potential biomarkers for AR-targeted treatments.

OBSERVATIONS The rate of AR positivity in breast cancer is about 60% to 80%. Biologically, the
AR pathway has cross-talk with several other key signaling pathways, including the
PI3K/Akt/mTOR and MAPK pathways, and with other receptors, including estrogen receptor and
human epidermal growth factor receptor-2. The value of AR positivity as a prognostic marker has
not yet been defined. Androgen receptor–targeted therapies, including AR agonists, AR
antagonists, and PI3K inhibitors, have shown promising results in clinical trials in patients with
Author Affiliations: Section of
breast cancer, and combinations of AR-targeted therapies with other agents have been
Translational Breast Cancer Research,
investigated for overcoming resistance to AR-targeted therapies. Biomarkers to stratify patients Department of Breast Medical
according to the likelihood of response to AR-targeted drugs are yet to be established. Potential Oncology, The University of Texas MD
biomarkers of response to AR inhibitors include AR phosphorylation and AR gene expression. Anderson Cancer Center, Houston
(Kono, Fujii, Lim, Karuturi, Tripathy,
Ueno); Morgan Welch Inflammatory
CONCLUSIONS AND RELEVANCE Androgen receptor–targeted treatments for breast cancer are Breast Cancer Research Program and
in development and have shown promising preliminary results. In-depth understanding of AR Clinic, The University of Texas MD
and AR-related signaling pathways would improve the treatment strategies for AR-positive Anderson Cancer Center, Houston
(Kono, Fujii, Lim, Tripathy, Ueno).
breast cancer. Further preclinical and clinical studies of AR-targeted drugs alone and in
Corresponding Author: Naoto T.
combination with other drugs are justified and warranted to clarify the biology of AR and Ueno, MD, PhD, FACP, Section of
inform the development of AR-targeted therapies to improve survival outcome in patients Translational Breast Cancer Research,
with breast cancer. Department of Breast Medical
Oncology, The University of Texas
MD Anderson Cancer Center, 1515
JAMA Oncol. 2017;3(9):1266-1273. doi:10.1001/jamaoncol.2016.4975 Holcombe Blvd, Unit 1354,
Published online March 16, 2017. Houston, TX 77030
(nueno@mdanderson.org).

T
he androgen receptor (AR) pathway has recently received in-
creasedattentionasapotentialtargetinbreastcancerforsev-
eral reasons, which include the development of newer and
better-tolerated AR-targeted agents in prostate cancer, an increasing
body of literature providing biological insight into the luminal AR (LAR)
subtype of triple-negative breast cancer (TNBC), and more studies ex-
ploring the connection between the hormone receptor and AR
pathways.1,2 Several retrospective clinical studies3-8 have shown that
AR might be a prognostic or predictive factor in breast cancer. At pres-
ent, the biggest areas of uncertainty related to AR as a potential thera-
peutictargetinbreastcancerarehowtoidentifythepatientsmostlikely
tobenefitfromAR-targetedtherapiesandhowtodeveloprationalcom-
binations of therapy based on AR-targeted therapies.
Herein, we discuss AR-related pathways, specific AR-targeted
therapies, and the development of predictive biomarkers to stratify
patients by likelihood of response to AR-targeted therapies.
Methods
We searched Medline, Embase, Web of Science, and Cochrane Li-
brary for articles written in English and published before December
2015 (see eFigure in the Supplement). Search terms were androgen
receptor, androgen, and anti-androgen alone or in combination with
search strings connected to the topics of interest—for example, breast
cancer, agonist, or antagonist. Furthermore, references cited in the re-
trieved articles were screened for additional articles. In addition, ab-
stracts from annual meetings from 2011 to 2015 of the American So-
ciety of Clinical Oncology, American Association for Cancer Research,
European Society of Medical Oncology, and San Antonio Breast Can-
cer Symposium were screened. ClinicalTrials.gov was searched for on-
going clinical trials. From these databases, 74 articles and abstracts and
19 clinical trials were included in this review.

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 Androgen Receptor–Targeted Therapies in Breast Cancer
Figure 1. Androgen Receptor (AR) Signaling Pathway in Breast Cancer
Cell membrane
Cytoplasm
Androgen
receptor
Hsp
N D L PI3K (PI3Kα, PI3Kβ)
Androgen GATA2
Hsp
Nucleus
N L
GATA2
D D
ARE GATA
The AR pathway has cross-talk with several other key signaling pathways,
including the PI3K/Akt/mTOR and MAPK pathways. AKT indicates AKT
serine/threonine kinase; ARE, androgen response element; D, DNA-binding
domain; EGFR, epidermal growth factor receptor; FOXA1, forkhead box protein
A1; GATA, GATA binding protein 2; Hsp, heat shock protein; L, ligand-binding
domain; mTOR, mammalian target of rapamycin; N, N-terminal domain;
Biology of AR and AR-Related Pathways
Androgen receptor consists of 4 domains, an N-terminal domain, a
DNA-binding domain, a hinge, and a ligand-binding domain, and
functions as a nuclear transcription factor.9 In the absence of li-
gand, AR attaches to heat shock proteins and is located mainly in
the cytoplasm.10 In the presence of ligand, the ligand-binding do-
main 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 coactivators, co-
repressors, and transcriptional modulators (Figure 1).9,11
Androgen receptor has been investigated extensively in pros-
tate cancer, and these studies have shown cross-talk of the AR path-
way with several other key signaling pathways, including the PI3K/
Akt/mTOR and MAPK pathways,11,12 and with several key proteins,
including Forkhead box protein A1 (FOXA1), phosphatase and ten-
sin homologue deleted on chromosome 10 (PTEN), PI3K, and re-
ceptor tyrosine kinases, including ERBB2 (formerly HER2 or HER2/
neu) and ERBB3 (Figure 1).13,14
High FOXA1 expression is commonly observed in breast cancer.15
In estrogen receptor–negative and AR-positive molecular apocrine
tumor cell lines, chromatin immunoprecipitation sequencing dem-
onstrated 98.1% overlap between the AR binding regions and ER
binding regions,16 and silencing of FOXA1 inhibited binding of AR to
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Review Clinical Review & Education
RTK (eg, ERBB2/ERBB3, EGFR)
Ras
AKT
Raf
mTOR
MEK
MAPK
β-Catenin
N L N L
FOXA1
D
PTEN WNT7B ERBB3
PTEN, phosphatase and tensin homologue deleted on chromosome 10;
RTK, receptor tyrosine kinase. The green zigzag-shaped object indicates
‘’stimulation’’ (the binding of WNT7B to the androgen receptor ‘’stimulates’’
nuclear translocation of β-catenin). The green oval outlines indicate GATA2
protein and heat shock protein.
chromatin and suppressed most of the genes regulated by AR.16 In
a series of 460 TNBCs, 15.2% coexpressed AR and FOXA1,17 and AR-
positive FOXA-positive tumors were significantly associated with
lower nuclear grade (33% vs 8%; P = .002) and ductal carcinoma in
situ (55% vs 32%; P = .02) than AR-positive FOXA-1 negative tumors,17
which suggests that FOXA1 expression might be associated with fa-
vorable characteristics in AR-positive tumors.
Other key proteins that mediate AR activation are discussed in
the subsections ERBB2-Positive Breast Cancer (ERBB22 and ERBB23)
and PI3K Pathway Inhibitors Combined with AR-Targeted Therapy
(PTEN and PI3K).
Prognostic and Predictive Value of AR Expression
by Breast Cancer Molecular Subtype
ER-Positive Breast Cancer
Approximately 70% to 90% of ER-positive tumors are also AR-
positive, depending on the definition of AR positivity.4,18
In ER-positive AR-positive cell lines, ligand-bound AR binds to
estrogen-related element in the nucleus, which leads to cell
apoptosis,19 whereas in ER-negative AR-positive cell lines, AR binds
to androgen-related element in the nucleus, leading to cell prolif-
eration (Figure 2).16 Several clinical studies confirmed this preclini-
cal finding, showing that among postmenopausal women, AR ex-
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 Clinical Review & Education Review
Figure 2. Association Between Estrogen Receptor (ER) and Androgen Receptor (AR) in Breast Cancer
CYP17A Inhibitors:
Abiraterone acetate orteronel
VT-464
Progesterone Testosterone
Estradiol
Cytoplasm
ER
Nucleus
Competition AR
FOXA1
ERE
E ARE
Ligand-bound AR competes with ligand-bound ER for binding to estrogen
response element (ERE) and leads to cell apoptosis in ER-positive and
AR-positive cell lines. AR binds to androgen response element (ARE) and leads
pression was a more favorable prognostic factor in women with ER-
positive breast cancer than in women with ER-negative breast
cancer.5,18 Moreover, a prospective study of 913 patients showed that
patients whose tumors had discordant ER and AR expression (ER-
positive AR-negative or ER-negative AR-positive) had a worse prog-
nosis than patients whose tumors had concordant ER and AR ex-
pression (ER-positive AR-positive or ER-negative AR-negative)
(adjusted hazard ratio [HR], 1.99; 95% CI, 1.28-3.10; P = .002).3
Some studies showed that AR positivity was a predictive marker
in ER-positive tumors. In a study of 192 patients with ER-positive
breast cancer treated with adjuvant tamoxifen, patients with a ra-
tio of nuclear AR to ER protein expression of at least 2.0 by immu-
nohistochemical staining had significantly shorter disease-free sur-
vival than patients with a ratio of less than 2.0 (HR, 4.4; 95% CI, 2.47-
7.83; P < .001),20 which suggested that AR overexpression was
associated with resistance to hormone therapy in ER-positive tu-
mors. This study also showed that inhibition of AR nuclear localiza-
tion by enzalutamide decreased not only androgen-mediated but
also estrogen-mediated tumor growth in both ER-positive AR-
positive and ER-negative AR-positive breast tumors.20 This finding
suggests the effectiveness of AR-targeted therapies for patients with
ER-negative AR-positive breast cancer and also patients with
ER-positive AR-positive breast cancer, including the 30% to 50% of
patients with ER-positive tumors that display de novo resistance to
traditional endocrine therapies.21
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Androgen Receptor–Targeted Therapies in Breast Cancer
DHT
Inhibitors:
AZD-5312
EZN-4176
pTVG-AR
AR Inhibitors:
Enzalutamide
ARN-509
ODM-201
AZD-3514
EPI-001
Inhibitor: Bicalutamide
AR
to cell proliferation, which is inhibited by AR agonists in ER-negative and
AR-positive cell lines. DHT indicates dihydrotestosterone; FOXA1, forkhead box
protein A1; the bold X’s mean “inhibit.”
ERBB2-Positive Breast Cancer
Approximately 60% of ERBB2-positive breast cancers overex-
press AR. 4,5 In ERBB2-positive breast cancer, AR positivity,
defined as 10% or more of cells with nuclear AR staining, was
associated with a higher frequency of ER and progesterone
receptor expression, smaller tumor size, earlier clinical stage, and
lower Ki-67 level compared with AR negativity. These findings
suggest that ERBB2 and AR coexpression might be associated
with less aggressive tumor subtype.22
In ER-negative ERBB2-positive breast cancer cells, binding
of WNT7B to AR leads to nuclear translocation of β-catenin
with androgen stimulation, and AR/FOXA1/β-catenin binding
to regulatory regions of the ERBB3 gene induces tumor
growth (Figure 1). 6 Indeed, our group found that AR-positive
TNBC cell lines have elevated ERBB2 expression level by
reverse-phase protein array compared with AR-negative
TNBC cells (unpublished observations). This suggests that prolif-
eration of AR-positive cells may be mediated via ERBB2/ERK1/2
signaling in breast cancer and that AR inhibitor may inhibit
proliferation of ER-negative ERBB2-positive AR-positive breast
cancers by blocking androgen-stimulated oncogenic ERBB2/
ERBB3 signaling. Taken together, these findings suggest that
the AR pathway is also important in ERBB2-positive breast cancer
and therefore needs to be explored to support further drug
development.
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 Androgen Receptor–Targeted Therapies in Breast Cancer
Triple-Negative Breast Cancer
Approximately 10% to 35% of TNBCs overexpresses AR, depend-
ing on the definition of AR positivity.1,23 A retrospective study of 699
patients with TNBC showed that disease-free survival was signifi-
cantly better in patients with AR-positive tumors than in those with
AR-negative tumors.24 Another study showed that compared with
AR-negative breast cancers, AR-positive breast cancers were asso-
ciated with better disease-free survival (P = .054) and overall sur-
vival (P = .04) despite a significantly lower rate of pathological com-
plete response to neoadjuvant chemotherapy (AR-positive 12.8%
vs AR-negative 25.4%; P < .001),25 which is similar to what has been
observed for ER-positive compared with ER-negative breast
cancers.
In the LAR subtype of TNBC, the level of AR was on average 9
times as great as in other subtypes of TNBC.26 The LAR subtype was
associated with the highest overall survival rate despite having the
lowest rate of pathological complete response to neoadjuvant che-
motherapy (10% vs 28% for TNBC in general).27 Also, LAR TNBC
showed ER-regulated gene transcription.26 Thus, AR-targeted
therapy should be considered for patients with AR-positive TNBC.
AR-Targeted Therapies
Non–tissue-selective androgens, such as fluoxymesterone or dan-
azol, which were used for treatment of metastatic breast cancer in
the 1960s, fell out of use because of their adverse effects, such as
hirsutism, hoarseness, or alopecia28; incomplete understanding of
their underlying biology; and inability to identify the patients most
likely to benefit. Likewise, medroxyprogesterone acetate (MPA),
which was used for treatment of metastatic breast cancer in the early
1990s,29 fell out of use following the introduction of tamoxifen and
aromatase inhibitors.30 A study to evaluate the predictive value of
AR expression in advanced breast cancer treated with MPA showed
that AR levels in patients who responded to MPA were significantly
higher than those in patients who did not respond to it (P < .001).31
In contrast, a retrospective medical record review of patients with
ER-positive metastatic breast cancer that had progressed during con-
temporary hormonal therapy showed a 33% clinical benefit rate
(CBR) of fluoxymesterone regardless of the level of AR expression.32
AR Agonists
Selective AR modulators are a potential treatment option for breast
cancer. In the cell line MDA-MB-231, TNBC cells stably expressing
wild-type AR, treatment with the selective AR modulator enobo-
sarm showed inhibition of metastasis-promoting paracrine factors
such as interleukin 6 and matrix metalloproteinase 13 and subse-
quent migration and invasion.33 Clinical trials of 2 selective AR modu-
lators, enobosarm and GSK2849466, are ongoing (see eTable and
eReferences in the Supplement).
AR Antagonists
The AR antagonists, which are among the therapeutic agents most
commonly used to treat prostate cancer, include several catego-
ries of drugs, for example, AR inhibitors and CYP17A inhibitors.34
Many AR antagonists are currently being investigated in breast can-
cer in preclinical and clinical studies. Bicalutamide, a nonsteroidal
first-generation AR antagonist, interrupts DNA-binding domain bind-
ing to the androgen-related element (Figure 2).35 A phase 2 clinical
trial of bicalutamide in breast cancer showed a CBR at 6 months of
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Review Clinical Review & Education
19% (95% CI, 7%-39%) and a median progression-free survival du-
ration of 12 weeks (95% CI, 11-22 weeks) but no objective responses.1
However, acquired mutations in the ligand-binding domain of AR or
an increase in AR protein concentration causes resistance to
bicalutamide.36
Enzalutamide, a second-generation AR antagonist, inhibits
nuclear translocation, chromatin binding, and interactions with AR
coregulators (Figure 2).37 In a phase 2 study of 75 patients with meta-
static AR-positive TNBC, enzalutamide showed a CBR of 35% (95%
CI, 24%-46%) at 16 weeks, a CBR of 29% (95% CI, 20%-41%) at 24
weeks, and median progression-free survival of 14.7 weeks.2 Al-
though enzalutamide is overall safe and well tolerated,38 a clinical
trial in patients with prostate cancer showed that enzalutamide was
associated with central nervous system adverse events, such as sei-
zures and posterior reversible encephalopathy.38 Brain metastasis
is more common in breast cancer, which may indicate highly cen-
tral nervous system–adverse events associated with enzalutamide
in breast cancer.
A phase 1 study showed no drug interaction between enzalu-
tamide and fulvestrant and between enzalutamide and
exemestane.39 A phase 2 trial of enzalutamide and exemestane is
ongoing (NCT02007512). An advantage of ODM-201 over
enzalutamide is that ODM-201’s rate of penetration of the blood-
brain barrier was negligible in preclinical studies.40 In a phase 1 clinical
trial in prostate cancer, treatment with ODM-201 was well tolerated,
and preliminary results showed an antitumor effect.41 ARN-509
selectively binds AR and inhibits its nuclear translocation and DNA
binding to androgen-related element. ARN-509 does not exhibit AR
agonist properties and suppressed tumor growth more than
enzalutamide in preclinical models of castration-resistant prostate
cancer (CRPC).42 Although CRPC preclinical models showed that
ARN-509 penetrated the blood-brain barrier and bound to the
γ-aminobutyric acid receptor,42 no seizures were reported at any
dose level in a phase l study.43
Several other AR antagonists are under development. AZD-
3514, a selective AR downregulator, inhibits ligand-driven nuclear
translocation of AR and downregulates AR levels.44 EPI-001 inhib-
its the AF-1 region in the N-terminal domain of AR, which is respon-
sible for most of the transcriptional activity of AR.45 Also under de-
velopment are antisense oligonucleotides, which utilize a locked
structure to improve the binding affinity for mRNA and reduce oli-
gonucleotide length. EZN-4176 downregulates full-length AR and
some AR splice variants (AR-V7, AR-V12, AR-V13, and AR-V14).46
CYP17A inhibitors, such as abiraterone acetate, orteronel (TAK-
700), and VT-464 (Viamet), are also currently under investigation
in breast cancer. These drugs block androgen production by inhib-
iting 17α-hydroxylase or 17,20-lyase activity (Figure 3).47
PI3K Pathway Inhibitors Combined With AR-Targeted Therapy
The PIK3CA mutation rate is higher in AR-positive breast cancer than
in AR-negative breast cancer (40% vs 4%).48 Our group previously
reported that breast cancers with kinase domain PIK3CA hot spot
mutations expressed significantly higher levels of AR than did breast
cancers with helical domain PIK3CA mutations or wild-type PIK3CA
(P = .02 and P < .001, respectively).49 Another group reported that
PIK3CA mutations were significantly enriched among the LAR sub-
type (46.2% [6 of 13]) compared with all other subtypes of TNBC
(4.5% [4 of 89]) (P < .001).48 Whether the specific subcategory of
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 Clinical Review & Education Review
Figure 3. Androgen Biosynthesis and CYP17A Inhibitors
Cholesterol CYP17A1 inhibitors
CYP17A1
17α-Hydroxylase 17,20-Lyase
17OH
Pregnenolone
Pregnenolone
HSD3B2 HSD3B2
17α-Hydroxylase 17,20-Lyase
17OH
Progesterone
Progesterone
5α-Reductase
Dihydroprogesterone
PI3K is important is less well known. Several studies have shown that
PI3Kα isoform is dominant in tumors with PIK3CA mutation,50 while
PI3Kβ is dominant in tumors with PTEN aberration.51 One study
showed that a selective PI3Kβ inhibitor blocks both PI3K pathway
activation and oncogenic transformation induced by PTEN
deficiency.51 Another study showed that all metastatic lesions that
initially responded to a PI3Kα inhibitor, BYL719, but subsequently
developed resistance had PTEN deficiency.50 In PTEN-mutated
breast cancer cell lines, inhibition of PI3Kβ induces PI3Kα kinase ac-
tivity, which causes rebound of Akt/mTOR signaling. Subse-
quently, inhibition of Akt/mTOR signaling reactivates the expres-
sion and/or activation of receptor tyrosine kinases, which causes AR
activation.14,52 Conversely, in cell lines with wild-type PTEN, PI3Kβ
inhibition did not induce downregulation of PI3K signaling. In in vitro
and in vivo experiments using PTEN-mutated prostate cancer cells,
suppressing both AR and PI3K led to suppression of tumor growth
and induction of cell apoptosis more than suppressing PI3K or AR
alone.14 These results suggest that in patients with AR-positive breast
cancer, the combination of PI3Kβ selective inhibitor and AR inhibi-
tor could be effective against tumors with PTEN deficiency or PTEN
mutation, while the combination of PI3Kα selective inhibitor and AR
inhibitor could be effective against tumors with PIK3CA mutation.
GATA binding protein 2 (GATA2) is activated by Akt, is en-
riched within AR-ligand binding regions,53 and inhibits AR and PTEN
in breast cancer (Figure 1).54 In whole-genome transcriptome data
sets, box and whisker plots analysis showed that GATA2 expres-
sion was significantly higher in breast cancer tissue than in normal
breast tissue (P = .004) while PTEN expression was significantly
lower in breast cancer tissue than in normal breast tissue (P < .001).53
Thus, PI3Kβ inhibitors may be reasonable agents for AR-positive
breast cancer with GATA2 expression. Preclinical data showed AR-
positive breast cancer cell lines are highly sensitive to a newly de-
veloped dual PI3K/mTOR inhibitor, NVP-BEZ235, compared with AR-
breast cancer cell lines. 26,55 Preclinical studies showed that
dihydrotestosterone and NVP-BEZ235 combination therapies
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Androgen Receptor–Targeted Therapies in Breast Cancer
Dihydroepiandrosterone
HSD3B2
Testosterone
5α-Reductase
CYP17A inhibitors block androgen
Dihydrotestosterone production by inhibiting
(DHT) 17α-hydroxylase or 17,20-lyase
activity.
achieved tumor regression compared with either drug alone in ER-
positive AR-positive mice,55 and LAR TNBC cell lines stimulated by
dihydrotestosterone had increased PI3K pathway activity and were
sensitive to PI3K/TOR pathway inhibitors.48
Immunotherapy
Data regarding association between AR and immune response are
limited. Patients with non–AR-driven enzalutamide-resistant pros-
tate cancer had significantly more programmed death-ligand (PD-
L1)-positive and PD-L2-positive dendritic cells in blood than did pa-
tients who responded to the drug or had never been treated with
it,56 which suggests that enzalutamide resistance that is indepen-
dent of AR reactivation may be overcome by anti–programmed
death-1 therapy.
The combination of enzalutamide and Twist vaccine in mouse
prostate cancer increased overall survival compared with treat-
ment with enzalutamide or Twist vaccine alone, and the benefit was
seen in advanced-stage prostate tumors.57
Biomarkers of Response to AR Inhibitors
Immunohistochemical staining is widely used to define AR positiv-
ity in breast cancer.8 However, it is not known what cutoff value
should be used to predict the response to AR-targeted therapy in
breast cancer. Androgen receptor phosphorylation status and AR
gene expression status may be predictive markers for AR-targeted
therapy.
AR Phosphorylation
Several phosphorylation sites have been identified in the AR mol-
ecule. The mechanism and function of phosphorylation vary accord-
ing to the site.58 For example, phosphorylation at Ser650 can be me-
diated by both hormone-dependent and hormone-independent
mechanisms (by androgen, protein kinase A, epidermal growth fac-
tor, and protein kinase C).59 Ser650 phosphorylation led to AR
nuclear localization regulated by stress kinase signaling pathways
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 Androgen Receptor–Targeted Therapies in Breast Cancer Review Clinical Review & Education

(MKK4/JNK and MKK6/p38) but antagonized AR transcription.60 In
another in vitro study,61 Ser210 and Ser791 phosphorylation acti-
vated by Akt-induced ERBB2 and conversely activated ERBB2 -in-
duced PIK3-Akt pathway activity.
Little is known regarding the role of AR phosphorylation in re-
sponse to AR-targeted therapy; further investigation of this topic is
warranted.
AR Gene Expression
Parker et al62 investigated whether gene expression profiling might
be superior to immunohistochemical analysis of AR expression for
predicting response to AR-targeted therapy. On the basis of results
of hierarchical clustering analysis using gene expression signatures
of 177 samples from 173 unique patients, patients were clustered into
2 groups: PREDICT AR–positive and PREDICT AR–negative. PRE-
DICT AR had 80% sensitivity and 65% specificity in prediction of
the CBR from enzalutamide at 16 weeks.62 PREDICT AR remained a
significant predictor after adjustment for number of prior chemo-
therapy regimens, age, immunohistochemical staining, and disease-
free interval in a multicovariate Cox proportional hazards model of
overall survival.63 Those results suggest that gene-based classifica-
tion might be a useful tool to predict the response to enzalutamide
in patients with metastatic TNBC.
Mechanisms of Resistance to AR Inhibitors
The mechanisms of resistance to AR inhibitors in breast cancer are
still not defined. However, some mechanisms of resistance to AR in-
hibitors have been identified in prostate cancer, and these may ap-
ply to breast cancer as well.
A recent review article64 on prostate cancer highlighted 3
mechanisms of acquired resistance to AR-targeted therapies: re-
stored AR signaling, AR bypass signaling, and complete AR inde-
pendence. Restored AR signaling results from point mutations within
the AR ligand-binding domain, such as H857Y and T878A, and from
AR splice variants. An example of the impact of point mutation is that
in the context of H875Y and T878A mutations, AR-targeted thera-
pies behave as AR agonists.65 Androgen receptor splice variant 7 (AR-
V7) mRNA is constitutively active and is the most abundant variant
detected in CRPC.66 AR-V7 mRNA in circulating tumor cells (CTCs)
in metastatic CRPC was predictive of primary resistance to enzalu-
tamide and abiraterone and was associated with shorter overall
survival.67 The second mechanism of acquired resistance to AR-
targeted therapies, AR bypass signaling, occurs when AR down-
stream signaling is activated by a related kinase not targeted by AR
inhibitors. This escape mechanism is similar to that of EGFR-
mutant lung cancer or BRAF-mutant melanoma.64 In prostate can-
cer, glucocorticoid receptor has been investigated as a potential re-
ceptor related to AR bypass signaling. Finally, some prostate cancer
has shown complete AR independence, as demonstrated by the ob-
served intrapatient and interpatient heterogeneity of AR expres-
sion in prostate tumors. Long-term usage of AR-targeted therapies
could cause an increase in the proportion of prostate cancer with
reduced or absent AR expression, so-called with loss of AR.64
In prostate cancer, higher proportions of AR-expressing CTCs
were associated with de novo resistance or acquired resistance to
AR-targeted therapies68; this finding has led to study of AR expres-
sion in CTCs in breast cancer.69 In CPRC, AR nuclear localization was
maintained after progression with the CYP17A inhibitor
abiraterone,70 and AR nuclear localization increased with increas-
ing lines of treatment.71 These findings suggest that greater AR
nuclear localization may be a marker of resistance to AR inhibitors.
Also in CPRC, posttreatment copy number variations in CYP17A1 or
AR in CTCs in patients treated with abiraterone were predictive of
early resistance to abiraterone and poor progression-free survival
and overall survival.72 Alterations in the ligand-binding domain of
AR detected on analysis of CTCs, including AR C-terminal loss, AR-
V7, and low AR-V7/C-terminal loss ratio, might be markers predict-
ing response to AR N-terminal-targeted therapies.73 As in prostate
cancer, understanding the mechanisms of resistance to AR inhibi-
tors in breast cancer will most likely lead to development of novel
effective combinations or novel predictive biomarkers.
Conclusions
Androgen receptor–targeted therapies have shown promising pre-
liminary results in breast cancer. The significant interaction of AR with
other signaling pathways and potential predictive markers for AR-
targeted therapies need to be investigated to identify the patients
with breast cancer most likely to benefit from AR-targeted thera-
pies, and the data reviewed herein suggest that combinations of AR-
targeted therapies with other therapies might have clinical rel-
evance in breast cancer. Given the new AR-targeted therapies and
the increasing investigation into their molecular mechanisms of ac-
tion, AR-targeted therapies may eventually lead to a breakthrough
in breast cancer treatment.

ARTICLE INFORMATION
Accepted for Publication: September 12, 2016.
Published Online: March 16, 2017.
doi:10.1001/jamaoncol.2016.4975
Author Contributions: Dr Ueno had full access to
all the data in the study and takes responsibility for
the integrity of the data and the accuracy of the
data analysis. Drs Kono and Fujii contributed
equally to this work.
Concept and design: Kono, Fujii, Ueno.
Acquisition, analysis, or interpretation of data: All
authors.
Drafting of the manuscript: Kono, Fujii, Karuturi,
Tripathy.
Critical revision of the manuscript for important
intellectual content: All authors.
Administrative, technical, or material support:
Tripathy, Ueno.
Study supervision: Kono, Fujii, Lim, Karuturi, Ueno.
Conflict of Interest Disclosures: Dr Karuturi has
received research grants from Novartis and
AstraZeneca for work unrelated to this manuscript.
No other disclosures are reported.
Funding/Support: This work was supported by the
Morgan Welch Inflammatory Breast Cancer
Research Program; a grant from the State of Texas
Rare and Aggressive Breast Cancer Research
Program; MD Anderson’s Cancer Center support
grant from the National Cancer Institute,
CA016672, which supports the Biostatistics Shared
Resource; National Cancer Institute grant
CA079466; and an award from the Japan Cancer
Society.
Role of the Funder/Sponsor: The funders had no
role in the design or conduct of the study;
collection, management, analysis, or interpretation
of the data; preparation, review, or approval of the
manuscript; or decision to submit the manuscript
for publication.
Additional Contributions: Stephanie P. Deming,
BA, of the Department of Scientific Publications at
MD Anderson Cancer Center provided scientific
editing services. Greg Pratt, DDS, clinical librarian of
the Research Medical Library at MD Anderson
Cancer Center, conducted the literature search.

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 Clinical Review & Education Review
They received no additional compensation beyond
their regular salaries.
REFERENCES
1. Gucalp A, Tolaney S, Isakoff SJ, et al; Translational
Breast Cancer Research Consortium (TBCRC 011).
Phase II trial of bicalutamide in patients with
androgen receptor-positive, estrogen
receptor-negative metastatic breast cancer. Clin
Cancer Res. 2013;19(19):5505-5512.
2. Traina AT, Miller K, Yardley AD, et al. Results from
a phase 2 study of enzalutamide (ENZA), an
androgen receptor (AR) inhibitor, in advanced AR+
triple-negative breast cancer (TNBC). 2015 ASCO
Annual Meeting. Abstract 1003.
3. Elebro K, Borgquist S, Simonsson M, et al.
Combined androgen and estrogen receptor status
in breast cancer: treatment prediction and
prognosis in a population-based prospective
cohort. Clin Cancer Res. 2015;21(16):3640-3650.
4. Collins LC, Cole KS, Marotti JD, Hu R, Schnitt SJ,
Tamimi RM. Androgen receptor expression in
breast cancer in relation to molecular phenotype:
results from the Nurses’ Health Study. Mod Pathol.
2011;24(7):924-931.
5. Park S, Koo JS, Kim MS, et al. Androgen receptor
expression is significantly associated with better
outcomes in estrogen receptor-positive breast
cancers. Ann Oncol. 2011;22(8):1755-1762.
6. Ni M, Chen Y, Lim E, et al. Targeting androgen
receptor in estrogen receptor-negative breast
cancer. Cancer Cell. 2011;20(1):119-131.
7. Yu Q, Niu Y, Liu N, et al. Expression of androgen
receptor in breast cancer and its significance as a
prognostic factor. Ann Oncol. 2011;22(6):1288-1294.
8. Vera-Badillo FE, Templeton AJ, de Gouveia P,
et al. Androgen receptor expression and outcomes
in early breast cancer: a systematic review and
meta-analysis. J Natl Cancer Inst. 2014;106(1):djt319.
9. Tan MH, Li J, Xu HE, Melcher K, Yong EL.
Androgen receptor: structure, role in prostate
cancer and drug discovery. Acta Pharmacol Sin.
2015;36(1):3-23.
10. Georget V, Térouanne B, Nicolas JC, Sultan C.
Mechanism of antiandrogen action: key role of
hsp90 in conformational change and
transcriptional activity of the androgen receptor.
Biochemistry. 2002;41(39):11824-11831.
11. Lattouf JB, Srinivasan R, Pinto PA, Linehan WM,
Neckers L. Mechanisms of disease: the role of
heat-shock protein 90 in genitourinary malignancy.
Nat Clin Pract Urol. 2006;3(11):590-601.
12. Sarker D, Reid AH, Yap TA, de Bono JS.
Targeting the PI3K/AKT pathway for the treatment
of prostate cancer. Clin Cancer Res. 2009;15(15):
4799-4805.
13. Naderi A, Meyer M, Dowhan DH.
Cross-regulation between FOXA1 and ErbB2
signaling in estrogen receptor-negative breast
cancer. Neoplasia. 2012;14(4):283-296.
14. Schwartz S, Wongvipat J, Trigwell CB, et al.
Feedback suppression of PI3Kα signaling in
PTEN-mutated tumors is relieved by selective
inhibition of PI3Kβ. Cancer Cell. 2015;27(1):109-122.
15. Lupien M, Eeckhoute J, Meyer CA, et al. FoxA1
translates epigenetic signatures into
enhancer-driven lineage-specific transcription. Cell.
2008;132(6):958-970.
1272 JAMA Oncology September 2017 Volume 3, Number 9 (Reprinted)
© 2017 American Medical Association. All rights reserved.
Downloaded From: https://jamanetwork.com/ by a Weill Cornell Medical Library User on 09/26/2019
Androgen Receptor–Targeted Therapies in Breast Cancer
16. Robinson JL, Macarthur S, Ross-Innes CS, et al.
Androgen receptor driven transcription in
molecular apocrine breast cancer is mediated by
FoxA1. EMBO J. 2011;30(15):3019-3027.
17. Guiu S, Charon-Barra C, Vernerey D, et al.
Coexpression of androgen receptor and FOXA1 in
nonmetastatic triple-negative breast cancer:
ancillary study from PACS08 trial. Future Oncol.
2015;11(16):2283-2297.
18. Hu R, Dawood S, Holmes MD, et al. Androgen
receptor expression and breast cancer survival in
postmenopausal women. Clin Cancer Res. 2011;17
(7):1867-1874.
19. Panet-Raymond V, Gottlieb B, Beitel LK, Pinsky
L, Trifiro MA. Interactions between androgen and
estrogen receptors and the effects on their
transactivational properties. Mol Cell Endocrinol.
2000;167(1-2):139-150.
20. Cochrane DR, Bernales S, Jacobsen BM, et al.
Role of the androgen receptor in breast cancer and
preclinical analysis of enzalutamide. Breast Cancer
Res. 2014;16(1):R7.
21. Lønning PE. Additive endocrine therapy for
advanced breast cancer: back to the future. Acta
Oncol. 2009;48(8):1092-1101.
22. Lin FdeM, Pincerato KM, Bacchi CE, Baracat EC,
Carvalho FM. Coordinated expression of oestrogen
and androgen receptors in HER2-positive breast
carcinomas: impact on proliferative activity. J Clin
Pathol. 2012;65(1):64-68.
23. Safarpour D, Pakneshan S, Tavassoli FA.
Androgen receptor (AR) expression in 400 breast
carcinomas: is routine AR assessment justified? Am
J Cancer Res. 2014;4(4):353-368.
24. Thike AA, Yong-Zheng Chong L, Cheok PY, et al.
Loss of androgen receptor expression predicts early
recurrence in triple-negative and basal-like breast
cancer. Mod Pathol. 2014;27(3):352-360.
25. Loibl S, Müller BM, von Minckwitz G, et al.
Androgen receptor expression in primary breast
cancer and its predictive and prognostic value in
patients treated with neoadjuvant chemotherapy.
Breast Cancer Res Treat. 2011;130(2):477-487.
26. Lehmann BD, Bauer JA, Chen X, et al.
Identification of human triple-negative breast
cancer subtypes and preclinical models for
selection of targeted therapies. J Clin Invest. 2011;
121(7):2750-2767.
27. Masuda H, Baggerly KA, Wang Y, et al.
Differential response to neoadjuvant chemotherapy
among 7 triple-negative breast cancer molecular
subtypes. Clin Cancer Res. 2013;19(19):5533-5540.
28. Kennedy BJ. Fluoxymesterone therapy in
advanced breast cancer. N Engl J Med. 1958;259
(14):673-675.
29. Parazzini F, Colli E, Scatigna M, Tozzi L.
Treatment with tamoxifen and progestins for
metastatic breast cancer in postmenopausal
women: a quantitative review of published
randomized clinical trials. Oncology. 1993;50(6):
483-489.
30. Ingle JN, Twito DI, Schaid DJ, et al.
Combination hormonal therapy with tamoxifen plus
fluoxymesterone versus tamoxifen alone in
postmenopausal women with metastatic breast
cancer: an updated analysis. Cancer. 1991;67(4):
886-891.
31. Birrell SN, Roder DM, Horsfall DJ, Bentel JM,
Tilley WD. Medroxyprogesterone acetate therapy in
advanced breast cancer: the predictive value of
androgen receptor expression. J Clin Oncol. 1995;13
(7):1572-1577.
32. Kono M, Fujii T, Lyons RG, et al. Impact of
androgen receptor expression in fluoxymesterone-
treated estrogen receptor–positive metastatic
breast cancer refractory to contemporary hormonal
therapy. Breast Cancer Res Treat. 2016;160(1):101-
109.
33. Narayanan R, Ahn S, Cheney MD, et al.
Selective androgen receptor modulators (SARMs)
negatively regulate triple-negative breast cancer
growth and epithelial:mesenchymal stem cell
signaling. PLoS One. 2014;9(7):e103202.
34. Agarwal N, Di Lorenzo G, Sonpavde G,
Bellmunt J. New agents for prostate cancer. Ann
Oncol. 2014;25(9):1700-1709.
35. Masiello D, Cheng S, Bubley GJ, Lu ML, Balk SP.
Bicalutamide functions as an androgen receptor
antagonist by assembly of a transcriptionally
inactive receptor. J Biol Chem. 2002;277(29):
26321-26326.
36. Chen CD, Welsbie DS, Tran C, et al. Molecular
determinants of resistance to antiandrogen
therapy. Nat Med. 2004;10(1):33-39.
37. Tran C, Ouk S, Clegg NJ, et al. Development of a
second-generation antiandrogen for treatment of
advanced prostate cancer. Science. 2009;324
(5928):787-790.
38. Loriot Y, Miller K, Sternberg CN, et al. Effect of
enzalutamide on health-related quality of life, pain,
and skeletal-related events in asymptomatic and
minimally symptomatic, chemotherapy-naive
patients with metastatic castration-resistant
prostate cancer (PREVAIL): results from a
randomised, phase 3 trial. Lancet Oncol. 2015;16(5):
509-521.
39. Elias AD, Burris HA, Patel MR, et al.
MDV3100-08: a phase 1 study evaluating the safety
and pharmacokinetics of enzalutamide plus
fulvestrant in women with advanced hormone
receptor-positive breast cancer. 38th Annual
CTRC-AACR San Antonio Breast Cancer Symposium;
December 8-12, 2015; San Antonio, TX. Abstract
P1-16-05. doi:10.1158/1538-7445
40. Moilanen AM, Riikonen R, Oksala R, et al.
Discovery of ODM-201, a new-generation androgen
receptor inhibitor targeting resistance mechanisms
to androgen signaling-directed prostate cancer
therapies. Sci Rep. 2015;5:12007.
41. Massard C, Penttinen HM, Vjaters E, et al.
Pharmacokinetics, antitumor activity, and safety of
ODM-201 in patients with chemotherapy-naive
metastatic castration-resistant prostate cancer: an
open-label phase 1 study. Eur Urol. 2016;69(5):834-
840.
42. Clegg NJ, Wongvipat J, Joseph JD, et al.
ARN-509: a novel antiandrogen for prostate cancer
treatment. Cancer Res. 2012;72(6):1494-1503.
43. Rathkopf DE, Morris MJ, Fox JJ, et al. Phase I
study of ARN-509, a novel antiandrogen, in the
treatment of castration-resistant prostate cancer.
J Clin Oncol. 2013;31(28):3525-3530.
44. Loddick SA, Ross SJ, Thomason AG, et al.
AZD3514: a small molecule that modulates
androgen receptor signaling and function in vitro
and in vivo. Mol Cancer Ther. 2013;12(9):1715-1727.
jamaoncology.com
 Androgen Receptor–Targeted Therapies in Breast Cancer
45. Brand LJ, Olson ME, Ravindranathan P, et al.
EPI-001 is a selective peroxisome
proliferator-activated receptor-gamma modulator
with inhibitory effects on androgen receptor
expression and activity in prostate cancer.
Oncotarget. 2015;6(6):3811-3824.
46. Dehm SM, Tindall DJ. Alternatively spliced
androgen receptor variants. Endocr Relat Cancer.
2011;18(5):R183-R196.
47. Toren PJ, Kim S, Pham S, et al. Anticancer
activity of a novel selective CYP17A1 inhibitor in
preclinical models of castrate-resistant prostate
cancer. Mol Cancer Ther. 2015;14(1):59-69.
48. Lehmann BD, Bauer JA, Schafer JM, et al.
PIK3CA mutations in androgen receptor-positive
triple negative breast cancer confer sensitivity to
the combination of PI3K and androgen receptor
inhibitors. Breast Cancer Res. 2014;16(4):406.
49. Gonzalez-Angulo AM, Stemke-Hale K, Palla SL,
et al. Androgen receptor levels and association with
PIK3CA mutations and prognosis in breast cancer.
Clin Cancer Res. 2009;15(7):2472-2478.
50. Juric D, Castel P, Griffith M, et al. Convergent
loss of PTEN leads to clinical resistance to a PI(3)Kα
inhibitor. Nature. 2015;518(7538):240-244.
51. Ni J, Liu Q, Xie S, et al. Functional
characterization of an isoform-selective inhibitor of
PI3K-p110β as a potential anticancer agent. Cancer
Discov. 2012;2(5):425-433.
52. Carver BS, Chapinski C, Wongvipat J, et al.
Reciprocal feedback regulation of PI3K and
androgen receptor signaling in PTEN-deficient
prostate cancer. Cancer Cell. 2011;19(5):575-586.
53. Masuda K, Werner T, Maheshwari S, et al.
Androgen receptor binding sites identified by a
GREF_GATA model. J Mol Biol. 2005;353(4):763-771.
54. Wang Y, He X, Ngeow J, Eng C. GATA2
negatively regulates PTEN by preventing nuclear
translocation of androgen receptor and by
androgen-independent suppression of PTEN
transcription in breast cancer. Hum Mol Genet.
2012;21(3):569-576.
55. Wang Y, Yu Q, He X, Romigh T, Altemus J, Eng
C. Activation of AR sensitizes breast carcinomas to
NVP-BEZ235's therapeutic effect mediated by
jamaoncology.com
© 2017 American Medical Association. All rights reserved.
Downloaded From: https://jamanetwork.com/ by a Weill Cornell Medical Library User on 09/26/2019
PTEN and KLLN upregulation. Mol Cancer Ther.
2014;13(2):517-527.
56. Bishop JL, Sio A, Angeles A, et al. PD-L1 is
highly expressed in Enzalutamide resistant prostate
cancer. Oncotarget. 2015;6(1):234-242.
57. Ardiani A, Farsaci B, Rogers CJ, et al.
Combination therapy with a second-generation
androgen receptor antagonist and a metastasis
vaccine improves survival in a spontaneous
prostate cancer model. Clin Cancer Res. 2013;19
(22):6205-6218.
58. Ward RD, Weigel NL. Steroid receptor
phosphorylation: assigning function to site-specific
phosphorylation. Biofactors. 2009;35(6):528-536.
59. Gioeli D, Black BE, Gordon V, et al. Stress kinase
signaling regulates androgen receptor
phosphorylation, transcription, and localization.
Mol Endocrinol. 2006;20(3):503-515.
60. Lange CA, Gioeli D, Hammes SR, Marker PC.
Integration of rapid signaling events with steroid
hormone receptor action in breast and prostate
cancer. Annu Rev Physiol. 2007;69:171-199.
61. Wen Y, Hu MC, Makino K, et al. HER-2/neu
promotes androgen-independent survival and
growth of prostate cancer cells through the Akt
pathway. Cancer Res. 2000;60(24):6841-6845.
62. Parker SJ, Peterson CA, Tudor CI, Hoffman J,
Uppal H; University of North Carolina, Chapel Hill;
Medivation Inc, San Francisco, CA. A novel
biomarker to predict sensitivity to enzalutamide
(ENZA) in TNBC. 2015 ASCO Annual Meeting.
Abstract 1083.
63. Cortes J, Crown J, Awada A, et al. Overall
survival (OS) from the phase 2 study of
enzalutamide (ENZA), an androgen receptor (AR)
signaling inhibitor, in AR+ advanced triple-negative
breast cancer (aTNBC). 2015 European Cancer
Congress. Abstract 1802.
64. Watson PA, Arora VK, Sawyers CL. Emerging
mechanisms of resistance to androgen receptor
inhibitors in prostate cancer. Nat Rev Cancer. 2015;
15(12):701-711.
65. Azad AA, Volik SV, Wyatt AW, et al. Androgen
receptor gene aberrations in circulating cell-free
DNA: biomarkers of therapeutic resistance in
(Reprinted) JAMA Oncology September 2017 Volume 3, Number 9
Review Clinical Review & Education
castration-resistant prostate cancer. Clin Cancer Res.
2015;21(10):2315-2324.
66. Hu R, Lu C, Mostaghel EA, et al. Distinct
transcriptional programs mediated by the
ligand-dependent full-length androgen receptor
and its splice variants in castration-resistant
prostate cancer. Cancer Res. 2012;72(14):3457-3462.
67. Antonarakis ES, Lu C, Wang H, et al. AR-V7 and
resistance to enzalutamide and abiraterone in
prostate cancer. N Engl J Med. 2014;371(11):1028-
1038.
68. Bambury RM, Louw J, Krupa R, et al.
Characteristics of de novo resistance to androgen
targeting therapeutics (AR Tx) through circulating
tumor cells (CTCs) analysis in metastatic castration
resistant prostate cancer (mCRPC) patients. Ann
Oncol. 2014;25(suppl 4):iv58-iv84. doi:10.1093
/annonc/mdu326
69. Fujii T,Ruben JM, Krupa R, et al. Androgen
receptor expression on circulating tumor cells
(CTCs) in metastatic breast cancer. AACR 2016.
Section 23, Board No. 13.
70. Crespo M, van Dalum G, Ferraldeschi R, et al.
Androgen receptor expression in circulating tumour
cells from castration-resistant prostate cancer
patients treated with novel endocrine agents. Br J
Cancer. 2015;112(7):1166-1174.
71. Scher H, Louw J, Krupa R, et al. Characterization
of circulating tumor cells (CTCs) of metastatic
castration resistant prostate cancer (mCRPC)
patients in first, second & third line systemic
therapies. Ann Oncol. 2014;25(suppl 4):iv58-iv84.
doi:10.1093/annonc/mdu326.
72. Salvi S, Casadio V, Conteduca V, et al.
Circulating cell-free AR and CYP17A1 copy number
variations may associate with outcome of
metastatic castration-resistant prostate cancer
patients treated with abiraterone. Br J Cancer.
2015;112(10):1717-1724.
73. Kelvin J, Lu D, Parker D, et al. Single cell analysis
of AR N terminal, AR C terminal and the ARv7 splice
variant in the CTCs of metastatic castration
resistant prostate cancer (mCRPC) patients. AACR
106th Annual Meeting 2015; April 18-22, 2015;
Philadelphia, PA.
1273