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Endocrine-RelatedCancer
ReviewM C Bruce et al. Kinome associated with
ER-positive status21 :5 R357–R370
The kinome associatedwith estrogenreceptor-positive status in humanbreast cancer
M Christine Bruce, Danielle McAllister and Leigh C Murphy
Department of Biochemistry and Medical Genetics, Manitoba Institute of Cell Biology, University of Manitoba
and CancerCare Manitoba, 675 McDermot Avenue, Winnipeg, Manitoba, Canada R3E 0V9
http://erc.endocrinology-journals.org q 2014 Society for EndocrinologyDOI: 10.1530/ERC-14-0232 Printed in Great Britain
Published by Bioscientifica Ltd.
Correspondence
should be addressed
to L C Murphy
Leigh.Murphy@
med.umanitoba.ca
Abstract
Estrogen receptor alpha (ERa) regulates and is regulated by kinases involved in several
functions associated with the hallmarks of cancer. The following literature review strongly
suggests that distinct kinomes exist for ERa-positive and -negative human breast cancers.
Importantly, consistent with the known heterogeneity of ERa-positive cancers, different
subgroups exist, which can be defined by different kinome signatures, which in turn are
correlated with clinical outcome. Strong evidence supports the interplay of kinase networks,
suggesting that targeting a single node may not be sufficient to inhibit the network.
Therefore, identifying the important hubs/nodes associated with each clinically relevant
kinome in ERC tumors could offer the ability to implement the best therapy options at
diagnosis, either endocrine therapy alone or together with other targeted therapies,
for improved overall outcome.
Key Words
" estrogen receptors
" breast cancer
" phosphorylation
" kinases
" endocrine therapy sensitivity
" biomarker
Endocrine-Related Cancer
(2014) 21, R357–R370
Introduction
The idea of personalized approaches to therapy in breast
cancer based on the molecular nature of the tumor can be
traced back to the late 1960s and early 1970s, when it was
discovered that some but not all human breast tumors
express estrogen receptors (ERs; Jensen et al. 1971). This
heralded the beginning of an era of targeted therapies for
breast cancer, identified the first biomarker used clinically
to predict the biological behavior of breast cancer, and
established the beginnings of understanding molecular
mechanisms by which the ovarian hormone, estrogen,
drives the growth and survival of the majority of human
breast cancers (Jensen & Jordan 2003), at least initially.
Inhibiting the activity of ERs with the antiestrogen
tamoxifen was the first targeted therapy in breast cancer.
Although the knowledge that female hormones were
involved in breast cancer and the hormonal/endocrine
therapy was used for breast cancer at least in the form of
ablation surgery such as ovariectomy dates back well over
a century, the identification of ERs in breast cancers
provided a molecular mechanism and rationale for the use
of hormonal therapies (Jensen & Jordan 2003). This led
directly to the development of the successful modern
endocrine therapies such as tamoxifen and other selective
estrogen receptor modulators (SERMs), which bind to the
ERs and induce conformational changes that modify and
in some cases inactivate the ERs (Jensen & Jordan 2003).
The newer endocrine therapies, the aromatase inhibitors
(AIs), which inhibit the aromatase enzyme, eliminate the
production of estrogen and therefore inhibit estrogen’s
proliferative action (Goss et al. 2011).
It was evident from the start that not all ERC breast
tumors were created equal. Although a little more than
Endocrine-RelatedCancer
Review M C Bruce et al. Kinome associated withER-positive status
21 :5 R358
70% of all breast tumors express ER, only about half of
patients with ERC tumors respond to tamoxifen. There-
fore, ERC breast cancers exhibit heterogeneity associated
with prognosis and treatment outcomes. The first step to
resolve this heterogeneity came from the idea that the
measurement of a downstream target of estrogen-
dependent ER signaling such as the progesterone receptor
(PR) would increase confidence that the pathway was
intact (Horwitz et al. 1975). This increased the accuracy of
treatment prediction, but was obviously still imprecise as
some 20–30% of ERC/PRC tumors are de novo resistant to
the endocrine therapies. Furthermore, initial response to
endocrine therapies is often followed by acquired resist-
ance despite the continued expression of ER (Encarnacion
et al. 1993, Bachleitner-Hofmann et al. 2002).
The next significant insight into the heterogeneity of
ERC breast cancer came with the identification of HER2
(ERBB2) amplification. Approximately 20% of all breast
cancers have amplified, overexpressed HER2, and 40–50%
of these will also be ERC. Interestingly, ERC/HER2C
tumors are more likely to be resistant to endocrine
therapy, in particular tamoxifen, thus providing
important insight into the relevance of crosstalk of
signaling pathways initiated at the level of the plasma
membrane with many aspects of the ER signaling
pathway. This may cause ligand-independent activation
of ER signaling and hormone therapy resistance.
The molecular detailing that has become possible
through the Human Genome Project and new high-
throughput/high-content technologies in the last decade
initially established five intrinsic molecular subgroups
(Sorlie et al. 2003) of which three were significantly
populated with ERC tumors. Most recently, at least ten
molecular subgroups of human breast cancer have been
described (Curtis et al. 2012) and eight of these appeared to
be significantly populated with ERC tumors (Curtis et al.
2012). Associated with these studies has been the frequent
identification of kinases, either mutated and/or structurally
altered in large cohorts of breast tumors (Banerji et al. 2012,
Curtis et al. 2012, Shah et al. 2012, Stephens et al. 2012).
Some of these have also been found frequently altered and
associated with AI sensitivity (Ellis et al. 2012).
ER and its many coactivators are regulated by
phosphorylation as well as other post-translational
modifications (PTMs; Rowan et al. 2000, York et al. 2010,
Le Romancer et al. 2011, Zhang et al. 2013). The discovery
that the ER and its coactivators are substrates of several
kinases (enzymes causing phosphorylation of specific
substrates), which are regulated by signaling pathways
frequently mutated or structurally altered in breast cancer
http://erc.endocrinology-journals.org q 2014 Society for EndocrinologyDOI: 10.1530/ERC-14-0232 Printed in Great Britain
(Yamnik et al. 2009, Yamnik & Holz 2010, Murphy et al.
2011), as well as the demonstration that a clinically
relevant phosphorylation profile of ERs can be identified
in human breast cancer (Skliris et al. 2010a), suggests that
kinases and/or phosphatases associated with ERC breast
cancer could provide a wealth of potential drug targets to
complement existing endocrine therapies or generate new
endocrine therapies. The following is a review of kinases
that have been identified as associated with ER status in
breast tumors or those that have been implicated in the
regulation of estrogen signaling and/or modifying sensi-
tivity to estrogen and its antagonists in breast cancer.
Kinases identified as mutated or structurallyaltered in breast cancer in large breast cancercohorts
Genome-wide analyses of large cohorts of breast cancer
cases are providing detailed, comprehensive analyses of
genomic aberrations in breast cancer at a population level.
Some studies have also provided data concerning their
impact on clinical characteristics. These studies have
shown that many of the frequently altered (amplified,
fused, deleted, or mutated) genes encode kinases. Some of
these frequently altered genes, such as HER2, were
previously known but others, such as MAP3K1 and its
substrate MAP2K4, have not previously been identified to
have functional roles in breast cancer. However, given that
enzymes, kinases in particular, have proven to be clinically
efficacious therapeutic targets, a wealth of data has now
been generated not only to understand the complex
biology of the disease but also to identify new treatments
for specific cohorts.
The recently published METABRIC cohort of breast
cancers, in which 2000 individual breast cancers were
interrogated, identified ten integrative clusters, each with
distinct molecular characteristics associated with clinical
outcome (Curtis et al. 2012). Often, altered genes encoding
kinases and phosphatases dominate individual clusters
(Table 1). Furthermore, the original intrinsic subtypes, in
particular the ERC luminal A and luminal B (Perou et al.
2000, Ignatiadis & Sotiriou 2013) subtypes, have been
further subdivided due to the METABRIC study (Curtis et al.
2012, Dawson et al. 2013). Therefore, a brief description of
this follows as it relates to clusters that have significant
ERC components.
METABRIC integrative cluster 1 (IntClust1), represent-
ing 7% of breast cancer (Curtis et al. 2012, Dawson et al.
2013), contains predominantly ERC tumors with luminal B
features and is characterized by amplification of the
Published by Bioscientifica Ltd.
Table 1 Kinases and phosphatases altered in ERC-dominated
breast cancer clusters from METABRIC (Curtis et al. 2012,
Dawson et al. 2013)
METABRIC
integrative clusters
Kinases or phosphatases
identified Alteration
IntClust1 Ribosomal protein S6kinase 1 (RPS6KB1)
Amplification/overexpression
Protein phosphatase1D (PPM1D)
Amplification/overexpression
IntClust2 PAK1 Amplification/overexpression
PIK3CA MutationIntClust3 PIK3CA Mutation
MAP3K1 MutationIntClust5 HER2 Amplification/
overexpressionPIK3CA Mutation
IntClust6 FGFR1 AmplificationIntClust7 PI3K Mutation
MAP3K1 MutationIntClust8 MAP2K4 Mutation
PI3K MutationIntClust9 Regulatory subunit B
of proteinphosphatase 2alpha (PPP2R2A)
Deletion
Endocrine-RelatedCancer
Review M C Bruce et al. Kinome associated withER-positive status
21 :5 R359
17q23 region. Two genes in this amplicon associated with
increased expression are ribosomal protein S6 kinase beta 1
(RPS6KB1 and p70S6K1) and protein phosphatase 1D
(PPM1D). Interestingly, expression of both of these genes
has been shown to be regulated by estrogen in ERC breast
cancer cells at the transcriptional level (Han et al. 2009,
Yamnik et al. 2009, Yamnik & Holz 2010). In addition,
the protein product of RPS6KB1 (p70S6K1) has
been shown to phosphorylate ERa (Yamnik & Holz 2010)
and under IGF1 stimulation p70S6K1 can be
co-immunoprecipitated with ERa in ERC breast cancer
cells (Becker et al. 2011). PPM1D/Wip1 is known for its p53
inhibitory effects and, in ERC MCF7 cells, has been shown
to be regulated by estrogen and to increase the transcrip-
tional activity of ERa (ESR1) as well as other steroid hormone
receptors (Proia et al. 2006), possibly by modulating
phosphorylation of coactivators such as SRC1 and/or
p300/CBP (Proia et al. 2006).
Integrative cluster 2 (IntClust2), representing 4% of
breast tumors, is also dominated by ERC tumors with
characteristics of both luminal A and luminal B subtypes
(Dawson et al. 2013). Amplification of chromosome region
11q13/14 characterizes this cluster and high expression of
another kinase, PAK1, known to affect ERa phosphory-
lation and activity (Wang et al. 2002, Mazumdar & Kumar
2003, Holm et al. 2009, Kok et al. 2010) is associated with
http://erc.endocrinology-journals.org q 2014 Society for EndocrinologyDOI: 10.1530/ERC-14-0232 Printed in Great Britain
its amplification in this region. A high frequency (w50%)
of PI3K catalytic subunit p110a (PIK3CA) mutations is also
observed in this group.
ERC tumors with luminal A characteristics predo-
minate integrative cluster 3 (IntClust3), which represents
15% of all breast tumors (Dawson et al. 2013). Tumors in
this cluster tend to have few structural alterations, low
genomic instability, and usually an excellent prognosis.
Interestingly, they also have the highest frequency of
PIK3CA mutations (w58%). As well, similar to other
clusters dominated by ERC tumors, a high level of
MAP3K1 mutations (w15%) is observed in IntClust3.
IntClust5 represents 10% of all breast tumors and is
characterized by HER2 amplification with w42% of them
also expressing ERa (Dawson et al. 2013). Approximately
30% of tumors in this cohort also have PIK3CA mutations.
ERC tumors with overexpressed HER2 are more likely to
be resistant to endocrine therapies. One reason for this is
thought to be the constitutive activation of several kinases
downstream of HER2, such as ERK1/2, PI3K, and AKT, all
of which can phosphorylate ERa and several ER coacti-
vators to enhance the ligand-independent activity of ERa
as well as to enhance the agonist activity of tamoxifen
(Wu et al. 2005, Le Romancer et al. 2011).
IntClust6, representing 4% of breast tumors, is another
predominantly ERC group with both luminal A and
luminal B characteristics (Dawson et al. 2013). Tumors of this
group show amplification of the chromosome 8p12 locus and
are genomically unstable with an intermediate prognosis.
Less than 20% of tumors in this group have PIK3CA
mutations, which is low compared to other ERC groups.
The gene for FGFR1 is located in the chromosome 8p12
region. FGFR1 amplification and overexpression have been
directly linked to endocrine therapy resistance (Turner et al.
2010, Balko et al. 2012). FGFR1 also regulates several kinases
such as PI3K and AKT, which are known to phosphorylate
ERa and its coactivators (Le Romancer et al. 2011).
IntClust7 (10% of breast tumors) and IntClust8 (15%
of breast tumors) are mainly ERC groups and while similar
in many ways tumors in Intclust8 display higher genomic
instability, with an associated inferior prognosis than
tumors in IntClust7 (Dawson et al. 2013). Interestingly,
both again have a high frequency of PI3K (PIK3CA)
mutations. IntClust7 has a high frequency of MAP3K1
mutations and IntClust8 has the highest frequency of
MAP2K4 mutations, a downstream target of MAP3K1.
The structural alterations usually found in MAP3K1
and MAP2K4 are deletions and mutations associated
with loss of function (Teng et al. 1997, Pham et al. 2013),
suggesting that the pathways they regulate have
Published by Bioscientifica Ltd.
Endocrine-RelatedCancer
Review M C Bruce et al. Kinome associated withER-positive status
21 :5 R360
tumor-suppressor function. Steroid hormone receptor
signaling, including estrogen and androgen receptors,
shows crosstalk with MAP3K1 in some systems, and it is
the ERC tumors, in particular luminal A type, that have
the highest level of mutation and/or deletion of the
MAP3K1/MAP2K4 pathway (Pham et al. 2013). This
pathway has been implicated in cell death pathways,
which under normal conditions is important for mam-
mary gland involution, hence its loss of function in many
ERC breast cancers may in part be responsible for the
dissociation of estrogen-induced proliferative and survival
pathways from growth-inhibiting differentiation
pathways (Pham et al. 2013). This pathway has been
described as having a molecular switch type function
between survival and cell death, possibly dependent on
cell-type background, subcellular localization, and caspase
3 activity (Pham et al. 2013). Increased ERa expression
combined with a decreased activity of the MAP3K1/
MAP2K4 pathway may, in part, underlie the change in
the balance of estrogen signaling regulation of survival/
proliferation vs cell cycle inhibition that is often
associated with differentiation.
IntClust9 (7% of breast tumors) is characterized by
a high frequency of PPP2R2A deletions (Dawson et al.
2013). PPP2R2A is the regulatory subunit B of protein
phosphatase 2 alpha (PP2A). While IntClust9 contains a
mixture of intrinsic subtypes, its ERC members are mainly
of the luminal B type, and loss of PPP2R2A expression is
associated with a high mitotic index. Interestingly, PP2A
also has been implicated in the regulation of ERa
phosphorylation and activity (Lu et al. 2003a).
The above data underscore that distinctly altered
kinase and phosphatase mutation patterns occur frequently
in ERC breast cancer subgroups with altered clinical
outcome. This would support the idea that combining
endocrine therapies with other targeted therapies informed
by each subgroup’s distinct kinase pattern could provide
better clinical outcome for breast cancer patients.
Kinases associated with the PI3K/AKT/mTORand ER-positive breast cancer
METABRIC and similar studies (Curtis et al. 2012, Ellis et al.
2012, Stephens et al. 2012) as well as previous smaller scale
studies (Miller et al. 2010, 2011a,b) have identified the
frequent structural and mutational alterations in the
PI3K/AKT/mTOR pathway that occur in ERC breast cancer.
IntClust1, IntClust2, IntClust3, and IntClust5 (Dawson
et al. 2013) have w25, 50, 58, and 30% frequencies of
PIK3CA mutations respectively. IntClust7 and IntClust8
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also have a high frequency of PIK3CA mutations while by
contrast IntClust6 has less than a 20% frequency of PI3K
pathway mutations (Dawson et al. 2013).
Experimental and clinical data suggest that hyper-
activation of the PI3K/AKT/mTOR pathway is associated
with endocrine resistance. However, gain-of-function
PIK3CA mutations in ERC tumors are often associated
with good prognosis (Miller et al. 2011a). Such apparently
contradictory results may be due to complexities associ-
ated with feedforward and feedback mechanisms involved
in the PI3K/AKT/mTOR pathway and other alterations
co-occurring in regulators of the pathway. This latter idea
is supported by the finding that most often the associ-
ations of PIK3CA mutations with good outcome in ERC
tumors are restricted to those tumors that are also HER2
negative (Fu et al. 2013).
As discussed above, the PIK3CA gene, encoding the
PI3K catalytic subunit p110a, is one of the most frequently
mutated genes in ERC breast cancers (Dawson et al. 2013).
Many of the mutations occur in ‘hot spots’ with the most
frequent mutations being E542K, E545K (both in the
helical domain), and H1047R (in the kinase domain)
(Barbareschi et al. 2007). Generally, the mutations result in
constitutive activation of the kinase (Di Cosimo & Baselga
2009). As mentioned above, the published data largely
suggest that mutations in PIK3CA occur more frequently
in ERC breast cancer with good prognosis and may also be
associated with better clinical outcome in patients treated
with endocrine therapy (Di Cosimo & Baselga 2009, Miller
et al. 2011a). However, this is not a universal finding
(Cuorvo et al. 2014). Recent reviews have discussed this
aspect in detail (Fu et al. 2013).
AKT1 mutations, often associated with PI3K-inde-
pendent constitutive activity, occur in w4% of breast
cancers and are often associated with ERC tumors.
However, the relationship of AKT expression and/or
activation to outcome in breast cancer is inconsistent
(Badve et al. 2010, Aleskandarany et al. 2011). Consi-
dering that the different AKT isoforms have distinct
functions (Dillon & Muller 2010) and that a recent study
using proximity ligation assay (PLA) to distinguish
between pAKT1 and pAKT2 (Spears et al. 2012)
determined the former to be associated with poor
prognosis and the latter with better prognosis, it seems
possible that the relative levels of each isoform may
determine the final read out. Furthermore, the inability
to distinguish the different pAKT isoforms may, at least in
part, underlie the previous lack of consistency (Badve
et al. 2010, Aleskandarany et al. 2011) around their
association with breast cancer outcome.
Published by Bioscientifica Ltd.
Endocrine-RelatedCancer
Review M C Bruce et al. Kinome associated withER-positive status
21 :5 R361
Owing to the frequency with which components of the
PI3K/AKT/mTOR pathway are altered in ERC tumors, and
the fact that the pathway is a central hub receiving growth
and survival signals from many factors, the detailed
molecular nature of the pathway in different ERC tumors
may be important to guide appropriate therapy options.
Kinases associated with ER status byexpression analyses
Several studies have now been published in which different
kinase expression patterns were found in ERC vs other
clinical subtypes of breast cancer. Using publically available
RNA expression databases, Bianchini et al. (2010) identified
16 kinases that were overexpressed in ERC/HER2K breast
cancer biopsy samples. These were IGF1R, STK32B, ERBB4,
FGFR3, BMPR1B, MAST4, HSPB8, IKBKB, DCLK1, ERBB3,
STK39, MAP3K1, PTK6, PLK2, TEX14, and MST1. Kinases
uniquely overexpressed in ERK and HER2C breast cancer
subtypes were also identified. Two robust kinase clusters
were recognized: a mitosis metagene cluster (12 distinct
kinases) and an immune kinase cluster (15 distinct kinases),
which were present inall clinical subgroups. Overexpression
of kinases composing the mitosis metagene cluster was
mostly found in ERK tumors and was not prognostic in this
subgroup. However, ERC/HER2K tumors that presented a
high mitosis kinase score were associated with a worse
prognosis but showed a higher frequency of pathological
complete response (pCR)toneoadjuvantchemotherapy.On
the other hand, overexpression of kinases from the immune
kinase cluster was associated with better survival in
ERC/HER2K and HER2C subgroups. Interestingly, the
authors also observed that in ERC tumors, many of the
overexpressed kinases were transmembrane growth factor
receptors, while ERK tumors mostly overexpressed intra-
cellular kinases associated with cell proliferation (Bianchini
et al. 2010).
Finetti et al. (2008) undertook a genome-wide
expression analysis of a cohort of primary human breast
tumors focusing mainly on the basal and luminal A
intrinsic breast cancer subtypes. From this analysis, they
extracted kinase genes whose differential expression was
associated with a clinical outcome. Not unexpectedly,
there were substantial differences in the pattern of kinase
gene expression between the basal and the luminal
A intrinsic subtypes. Of more interest, however, was the
discovery that 16 kinases were overexpressed in most of
the basal group and in a few luminal A tumors. These
kinases were AURKA, AURKB, BUB1, BUB1B, CDC2 (CDK1),
CDC7, CHEK1, MASTL, MELK, NEK2, PBK, PLK1, PLK4,
http://erc.endocrinology-journals.org q 2014 Society for EndocrinologyDOI: 10.1530/ERC-14-0232 Printed in Great Britain
SRPK1, TTK, and VRK1. Many of these kinases have been
previously reported to be involved in the G2 and M phases
of the cell cycle (Malumbres & Barbacid 2009, Knight et al.
2010). Notably, these kinases include the 12 kinases
making up the mitosis metagene cluster identified by
Bianchini et al. (2010). Similarly, Finetti et al. (2008) found
that overexpression of kinases from this 16-kinase
signature in luminal A (ERC) tumors was associated with
a poor clinical outcome. The association of mitosis and
proliferation signatures with poorer prognosis in the
luminal breast cancer subgroups is a consistent theme
(Ribelles et al. 2013).
Unique kinases associated with ER status in breast
cancer cell lines have also been reported (Michalides et al.
2002, Finetti et al. 2008, Midland et al. 2012), some of
which show overlap with studies in tumors (Finetti et al.
2008, Midland et al. 2012), therefore potentially providing
models of ERC breast cancer kinomes in vitro. These data
support the existence of distinct kinomes, not only
associated with ER status per se, but also further define
heterogeneity within ERC breast tumors.
Kinase overexpression associated withsensitivity to endocrine therapies
There are many different kinases that when either over-
expressed or underexpressed in ERC breast cancer cells
lead to altered cell growth and survival responses to both
SERMs such as estrogen and tamoxifen, and AIs. Many of
these are listed in Table 2.
Such data underscore the importance of kinase net-
works, as many of the kinases listed in Table 2 converge on
common hubs associated with cell growth, survival and
cell death. It is not surprising that the interaction of
multiple kinases with ER signaling is observed in breast
cancer, as many of these kinases are key components of
proliferation, survival and cell death pathways and would
be expected to be regulated by estrogen, through the ER,
which is the primary mitogenic/survival signal in the
majority of breast cancers, at least initially (Musgrove &
Sutherland 2009, Osborne & Schiff 2011).
In ERC breast cancer, gene signatures that are based on
proliferation often strongly correlate with Ki67 expression
(Gao et al. 2014), a well-known marker of proliferation.
Furthermore, in ERC breast tumors in particular, it is
Ki67 and not pCR that is the early correlative endpoint
for predicting efficacy of both hormonal therapy or
chemotherapy in ERC breast cancer (Yerushalmi et al.
2010, Dowsett et al. 2011, Ellis et al. 2011,
von Minckwitz et al. 2012, Gao et al. 2014). Recently, using
Published by Bioscientifica Ltd.
Table
2Kinasesexp
erimentallymanipulatedandshownto
influence
tamoxifen(Tam)oraromatase
inhibitor(A
I)sensitivity
Kinase
sGain
offu
nction
Loss
offu
nction
Refe
rence
sEffects
Clinicalco
rrelation
EGFR
Ectopic
ove
rexp
ression
Agthove
netal.(1992)
Tam-resistantgrowth
Yes(G
iltnaneetal.2007
HER2
Ectopic
ove
rexp
ression
Benzetal.(1992)
Tam-resistantgrowth
Yes(O
sborneetal.2003)
AKT
Ectopic
ove
rexp
ression
Campbelletal.(2001),
deGraffenriedetal.(2004)
andSilvaetal.(2007)
Tam-resistantgrowth
Yes(Perez-Te
norioetal.2002)
Akt3
Ectopic
ove
rexp
ression
Faridietal.(2003)
E2-independent,
Tam-stimulated
growth
asxe
nograft
Yes(N
akatanietal.1999)
ERK1/2
MAPK
Yes(G
eeetal.2001)
PKCa
Ectopic
ove
rexp
ression
Chisamore
etal.(2001)and
Frankeletal.(2007)
Tam-resistantgrowth
Yes(Kalstadetal.2010)
PKCd
Ectopic
ove
rexp
ression
Nabhaetal.(2005)
Tam-resistantgrowth
PKA
Ove
rexp
ressionbyreducing
exp
ressionofnegative
regulatory
subunit
PKA-RIalpha
Michalidesetal.(2004)
Tam-resistantgrowth
Yes(M
ichalidesetal.2004)
MKP3
Ectopic
ove
rexp
ression
Cuietal.(2006)
Tam-resistantgrowth
Yes(Cuietal.2006)
CDK10
siRNA
Iornsetal.(2008)
Tam-resistantgrowth
inhibition
Yes(Iornsetal.2008)
CRK7
siRNA
Iornsetal.(2009)
Tam-resistantgrowth
inhibition
No
IKK3
Ectopic
ove
rexp
ression
Guoetal.(2010)
Protectionagainst
Tam-inducedcell
death
No
SphK1
Ectopic
ove
rexp
ression
Sukoch
eva
etal.(2009)
Tam-resistantgrowth
inhibition
Yes(Ruckhaberleetal.2008)
c-ABL
siRNA
Zhaoetal.(2010)
Sensitize
scellsto
Tam
inhibition
Yes(Zhaoetal.2010)
Ronreceptortyrosine
kinase
(MST
1R)
Ectopic
ove
rexp
ression
McC
laineetal.(2010)
Tamoxifenresistance
No
EphA2receptortyrosine
kinase
(EPHA2)
Ectopic
ove
rexp
ression
Luetal.(2003b)
Tamoxifenresistance
Yes(Brantley-Sieders
etal.2011)
cRET
siRNA
Plaza
-Menach
oetal.(2010)
Increasedsensitivity
toTa
mYes(M
orandietal.2013)
HSP
B8
Ectopic
ove
rexp
ression
Gonza
lez-Malervaetal.(2011)
Tam
resistance
Yes(G
onza
lez-Malervaetal.
2011)
LMTK3
siRNA
Giamasetal.(2011)
Increasedsensitivity
toTa
mYes(G
iamasetal.2011)
IGF-R1
Ectopic
ove
rexp
ression
Zhangetal.(2011)
Tam
andfulvestrant
resistance
Yes(Foxetal.2011,W
inder
etal.2014)
FGFR
3Ectopic
ove
rexp
ression
Tomlinsonetal.(2012)
Tam
andfulvestrant
resistance
Yes(Tomlinsonetal.2012)
TBK1
Ectopic
ove
rexp
ression
Weietal.(2014)
Tam
resistance
Yes(W
eietal.2014)
Endocrine-RelatedCancer
Review M C Bruce et al. Kinome associated withER-positive status
21 :5 R362
http://erc.endocrinology-journals.org q 2014 Society for EndocrinologyDOI: 10.1530/ERC-14-0232 Printed in Great Britain
Published by Bioscientifica Ltd.
A/B
1
S46/47Y52
Y537S102 S118 S167 S236 T311S104 S212 S305
S559
S554
S282S154S106 Y219 S294
180 263 302 595
C D FE
Figure 1
Known phosphorylation sites on estrogen receptor a. Sites identified by
stars are those that have been determined in ERaC breast cancer cases in
the Manitoba Breast Tumor Bank (MBTB) and are the basis of the P7-ERa
score. The black stars are those residues which when phosphorylated are
associatedwith a good clinical outcome in patients treated with tamoxifen.
The open/white stars are those residues which when phosphorylated are
Endocrine-RelatedCancer
Review M C Bruce et al. Kinome associated withER-positive status
21 :5 R363
neoadjuvant antiestrogen therapy (particularly AIs), it
was observed that decreased detection of survival pathway
activation markers (e.g. phosphorylated AKT and phos-
phorylated mTOR) in tumors after treatment, compared
with pretreatment levels, was predictive of a better clinical
outcome (Generali et al. 2008, 2011), suggesting that
estrogen via the ER was regulating these pathways, directly
or indirectly in vivo. Many preclinical models have shown
that estrogen, via ER signaling, at least in part, regulates the
activities of PI3K/AKT/mTOR, p38MAPK, and MAPK/
ERK1/2 (Zhang et al. 2002, Lee et al. 2005, Yu & Henske
2006, Kazi et al. 2009, Maruani et al. 2012). This suggests that
the use of hormonal therapies in combination with the
most appropriately targeted kinase inhibitors may be more
beneficial at the onset of therapy than application in a
sequential fashion. Indeed, there are ongoing clinical trials
evaluating the use of combination therapies with endo-
crine therapies as first-line approaches (Ciruelos 2014).
A major challenge of using kinase inhibitors is that
kinase networks especially those associated with growth and
survival are often interconnected and inhibition of one may
have effects beyond the immediate targets. Adaptive
reprogramming of cancer kinomes due to single kinase
inhibitors has been demonstrated (Duncan et al. 2012) and
an argument for targeted combination therapy approaches
initially has been put forward (Stuhlmiller et al. 2014). The
development of resistance to hormonal therapies most
often occurs despite the continued expression of ERa
(Encarnacion et al. 1993, Bachleitner-Hofmann et al.
2002). In addition, many laboratory studies suggest that
adaptive responses of breast cancer cells, rather than
selection of existing ER-negative cells in the original
heterogeneous population, frequently occur (Santen et al.
2003, Browne et al. 2013). In such cases, increased
expression/activity of kinases also frequently occurs (Coutts
& Murphy 1998, Santen et al. 2003, 2004), supportive of the
concept that adaptive reprogramming of the breast cancer
kinome, in part, underlies some mechanisms of estrogen
independence and anti-estrogen resistance (Stuhlmiller
et al. 2014). The challenge will be to understand this and
its potential plasticity within the underlying heterogeneity
of ERC breast cancers and at the individual patient level.
associated with a poor clinical outcome in patients treated with tamoxifen
(Skliris et al. 2010a). It should be noted that others have determined that
S305 when phosphorylated is associated with a poor clinical outcome in
tamoxifen-treated patients (Le Romancer et al. 2011) and we have found
that tyrosine (Y) 537 when phosphorylated is also associated with a poor
clinical outcome in tamoxifen-treated patients (Skliris et al. 2010b). These
latter two results (textured stars) are consistent with our observation that
phosphorylation in N-terminal residues is associated with a good clinical
outcome, but phosphorylation in C-terminal residues is associated with a
poor clinical outcome.
Kinases known to phosphorylate ERa
In addition to ER signaling regulating kinase pathway
expression and/or activity, ER activity can also be
regulated by kinases.
ERa can be phosphorylated on many residues (Fig. 1)
and ERa has been identified as a substrate for several
http://erc.endocrinology-journals.org q 2014 Society for EndocrinologyDOI: 10.1530/ERC-14-0232 Printed in Great Britain
kinases with known functions in breast cancer develop-
ment and progression. Dysregulation including mutation
and structural alterations of kinases themselves or the
signaling pathways in which they function is thought, in
part, to contribute to the dysregulation of ER signaling
that is associated with the development of breast cancer as
well as its progression to endocrine resistance in vivo.
Multiple aspects of ER activity can be affected by
phosphorylation; however, the focus of the majority of
studies addressing this issue has been on the transcrip-
tional activity (Le Romancer et al. 2011) and, not
surprisingly, it has been observed that differential phos-
phorylation of ERa (e.g. PKA activation) can alter the
chromatin-binding pattern (cistrome) of the receptor, in
turn altering the ERa transcriptome (de Leeuw et al. 2013).
The function of phosphorylation on ER activity and that
of other steroid hormone receptors have been recently
extensively reviewed (Le Romancer et al. 2011, Trevino &
Weigel 2013) and will not be reviewed herein.
Multiple different kinases can phosphorylate the same
ERa residue (e.g. serine amino acid residue 167 (S167) can
be phosphorylated by AKT, p70S6K, Aurora A, and
p90RSK) (Le Romancer et al. 2011). Similarly, one kinase
can phosphorylate several different residues on ERa
(e.g. MAPK can phosphorylate S104/106, S118, and S167)
(Le Romancer et al. 2011). Many kinases known to
phosphorylate ERa can also phosphorylate various
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Endocrine-RelatedCancer
Review M C Bruce et al. Kinome associated withER-positive status
21 :5 R364
coactivators and coregulators (Wu et al. 2005), impacting
ER (ESR1) transcriptional activity. This provides a
potential mechanism allowing the integration of multiple
pathways to regulate the biology and/or patho-biology of
ERa in the mammary gland. Support for this idea, at least
in breast cancer, is provided by the existence of a
phosphorylation code for ERa (Skliris et al. 2010a) and at
least one of its coactivators, SRC3/AIB1 (Wu et al. 2004,
York et al. 2010). As ERa can undergo several other types of
PTMs, e.g. acetylation, methylation, ubiquitylation, etc.
(Le Romancer et al. 2011), one can envisage a broader ERa
PTM or epigenetic-like code.
The identification of kinases phosphorylating ERa has
been achieved using multiple methods, alone or in
combination: in vitro studies using recombinant proteins,
mass spectroscopy, the use of selective small-molecular-
weight kinase activators or inhibitors, and overexpression
or knockdown of expression using cells in culture or as
xenografts. Furthermore, it is reasonable to assume, while
not proving, that if ER can be directly phosphorylated by a
kinase, the two proteins would directly bind under
appropriate circumstances. Table 3 lists a number of kinases
that have been found to undergo protein:protein
interactions with ERa using different methodologies,
e.g. co-immunoprecipitation (Wierer et al. 2013) and
other pull-down-type assays (Kanaujiya et al. 2013), PLA
(Poulard et al. 2012), yeast-2-hybrid assay (Paul et al. 2014),
Table 3 Kinases shown to interact directly with estrogen receptor
Kinases Assays
ERK1/2 CoIP; ChIP/reChIPp70S6K1 Co-IPGSK3 Co-IPCDK2 GST pull-down, in vitro kinase assIKKa Co-IP ChIP-reChIPCDK7 In vitro Co-IPAKT In vitro kinase assayPI3K Proximity ligation assay Co-IPpp90RSK1 In vitro kinase assays Co-IPPKA FRET in vitro kinase assayILK GST-down experiments Co-IPEGFR Co-IP in vitro kinase assayIGFR Co-IPDNA-PK Co-IPcAbl Co-IP in vitro kinase assayCK2 In vitro kinase assayIKK3 Co-IP in vitro kinase assayPAK1 In vitro kinase assay GST-pull-dow
experiments Co-IPc-SRC Proximity ligation assay Co-IP in v
kinase assayp38 MAPK Immunocomplex kinase assay in v
kinase assay shows no phosphoPLK1 Co-IP ChIP/reChIP
http://erc.endocrinology-journals.org q 2014 Society for EndocrinologyDOI: 10.1530/ERC-14-0232 Printed in Great Britain
and fluorescence resonance energy transfer (FRET) (Zwart
et al. 2007a,b). Direct interaction of ERa with kinases can
occur in the cytoplasm (Poulard et al. 2012), at the plasma
membrane (Poulard et al. 2012), as well as in the nucleus on
chromatin (Madak-Erdogan et al. 2011, 2014, Wierer et al.
2013), with some methodologies, such as PLA, allowing the
determination of the subcellular localization of any
interactions that occur (Poulard et al. 2012).
There is no doubt that phosphorylation and other
PTMs (Wu et al. 2007, Le Romancer et al. 2011) are
important for the regulation of ER highlighted by the
existence of a phosphorylation code for ERa in human
breast tumors (Skliris et al. 2010a). However, it is still
unclear as to which kinases and phosphatases are involved
in regulating ERa in vivo. Correlations of expression and/or
activity of some kinases with ER or its phosphorylated
forms in human breast tumors have been reported,
supporting a possible role in vivo (Murphy et al. 2004,
Gee et al. 2005, Jiang et al. 2007, Shrivastav et al. 2014).
Many of the kinases that can directly phosphorylate
ERa and its coregulators can also be regulated by estrogen
signaling under some circumstances. Many such kinases are
components of key signaling pathways involved in
development/differentiation, proliferation, cell cycle,
motility/invasion, and cell death. Whether or not they are
regulated by estrogen or in turn regulate ERa may depend on
levels of expression of both substrate and kinase, and on
a
References
Madak-Erdogan et al. (2011)Becker et al. (2011)Medunjanin et al. (2005)
ay Rogatsky et al. (1999)Park et al. (2005)Chen et al. (2000)Campbell et al. (2001) and Sun et al. (2001)Sun et al. (2001) and Poulard et al. (2012)Joel et al. (1998)Chen et al. (1999), Zwart et al. (2007a,b)Acconcia et al. (2006)Marquez et al. (2001)Mendez et al. (2003)Medunjanin et al. (2010)He et al. (2010)Williams et al. (2009)Guo et al. (2010)
n Wang et al. (2002)
itro Arnold et al. (1995b, Poulard et al. (2012) andSun et al. (2012))
itrorylation
Lee & Bai (2002)
Wierer et al. (2013)
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Endocrine-RelatedCancer
Review M C Bruce et al. Kinome associated withER-positive status
21 :5 R365
mutations or structural alterations that may eliminate or
introduce new regulatory factors. The ability of the
estrogen/ERa complex to activate kinases that in turn
can phosphorylate ER and modify function provides a
powerful feed-forward amplification system that may
drive many human breast cancers. Understanding how
this occurs and how it can be perturbed to drive
progression to therapy resistance would provide funda-
mental information to inform early combination
approaches, for preventing and/or treating resistant tumors.
Interestingly, although in primary breast tumors, few
ERa mutations have been found, one known mutation
K303R changes the amino acid lysine that can be
acetylated (another type of PTM) to an arginine residue
that cannot be acetylated. This in turn alters regulation of
S305 phosphorylation on ERa, a site of ERa phosphory-
lation with established relevance in vivo and in AI
resistance (Herynk & Fuqua 2004, Barone et al. 2010).
There are also other examples of the co-regulation of
phosphorylation with other PTMs to regulate ERa
expression and/or activity. For example, c-Src can phos-
phorylate ERa at Y537 that in turn facilitates its
interaction with E3 ubiquitin ligases such as E6AP,
resulting in ubiquitin-dependent degradation of ERa
(Zhou & Slingerland 2014). Most recently, however,
frequent somatic mutations in ERa have been identified
in metastases from ERC breast cancer. This is more
frequently associated with metastases that occur during
or following endocrine therapy (Zhang et al. 1997,
Robinson et al. 2013, Jeselsohn et al. 2014, Segal & Dowsett
2014). The most frequent mutation identified was at Y537
or the residue beside it, D538; therefore, affecting directly
or indirectly a well-known phosphorylation site on ERa
(Arnold et al. 1995a, Nettles et al. 2008, Skliris et al. 2010b)
with known clinical relevance (Skliris et al. 2010b). Such
data underscore the importance of ERa phosphorylation
and other PTMs to breast cancer progression.
Our understanding of estrogen-regulated ERa signaling
in human breast cells comes from model systems that are all
cancer cells. Moreover, all ERC and ERK cell lines were
originally obtained from breast cancer metastases usually
pleural and ascitic effusions (Soule et al. 1973, Lippman
et al. 1976). We have little if any understanding of ERa
signaling in normal human breast epithelial cells, mainly
due to the lack of appropriate ERC models. This remains a
large gap in our understanding, potentially limiting the
development of more efficacious prevention strategies. This
is especially important as increased ERa expression in
normal human breast is associated with an increased cancer
risk (Khan et al. 2005) and elevated ERa expression is one of
http://erc.endocrinology-journals.org q 2014 Society for EndocrinologyDOI: 10.1530/ERC-14-0232 Printed in Great Britain
the earliest alterations occurring in ‘precursors’ of breast
cancer (Shoker et al. 1999, Lee et al. 2006). ERa is highly
expressed in most atypical ductal hyperplasia (ADH), ductal
carcinoma in situ (DCIS), and invasive breast cancers
(Shoker et al. 1999, Allred et al. 2001). However, the
mechanisms leading to increased ERa expression during
tumorigenesis are poorly understood. Interestingly, beside
alterations in ER gene transcription (Muscat et al. 2013),
altered kinase expression affecting ERa protein stability has
been suggested (Henrich et al. 2003, Antoon et al. 2013)
and, therefore, highlights the potential link between
phosphorylation and estrogen signaling.
The challenge now is to identify those kinases and
their associated networks that phosphorylate and regulate
ERa function in ERC tumors and potentially normal
breast in vivo, as such information will identify the most
efficacious targeted treatment approaches upfront and
may inform better prevention approaches.
Conclusions
ERa regulates and is regulated by kinases involved in several
functions associated with the hallmarks of cancer (Hanahan
& Weinberg 2011). The presence of a phosphorylation code
for ERa in breast cancers associated with clinical outcome
(Skliris et al. 2010a) and the knowledge that there are also
other PTMs associated with ERa (Le Romancer et al. 2011)
in vivo suggest that there is an epigenetic-like code for ERa,
which can regulate and is in part regulated by distinct
kinomes. The literature reviewed above strongly suggests that
distinct kinomes exist for ER-positive and -negative breast
cancers. Even within ERC cancers, different subgroups exist,
defined by different kinome signatures, which can be
correlated with clinical outcome. Strong evidence supports
the interplay of kinase networks, suggesting that targeting a
single node may not be sufficient to inhibit the network.
Therefore, identifying the important hubs/nodes associated
with each clinically relevant kinome in ERC tumors could
offer the ability to implement the best therapy options at
diagnosis, either endocrine therapy alone or together with
other targeted therapies for an improved overall outcome.
Declaration of interest
The authors declare that there is no conflict of interest that could be
perceived as prejudicing the impartiality of the review.
Funding
This work was made possible through grant support to L C Murphy from the
Canadian Institutes of Health Research (CIHR), the Canadian Breast Cancer
Foundation (CBCF), and the Canadian Cancer Society Research Institute
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Endocrine-RelatedCancer
Review M C Bruce et al. Kinome associated withER-positive status
21 :5 R366
(CCSRI). M C Bruce is funded by a CBCF-Prairies/NWT region Postdoctoral
Fellowship. Morerover, some of published works referred to in this review
used breast tumor samples from theManitoba Breast Tumor Bank, a member
of the Canadian Tumor Repository Network, which are funded in part by the
CancerCare Manitoba Foundation (CCMF) and CIHR, respectively.
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Received in final form 9 July 2014Accepted 23 July 2014Made available online as an Accepted Preprint23 July 2014
Published by Bioscientifica Ltd.
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