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Steroid receptor coactivator-3 (SRC-3), localized in a frequently amplified chromosomal region,
20q12[1], was first identified as Amplified in Breast cancer 1 (AIB1), also known as NCoA3,
p/CIP[2], RAC3[3],
ACTR[4], and TRAM1[5]. Biochemical
and cellular biological analyses revealed that
SRC-3 belongs to the p160 steroid receptor coactivator family, which includes
SRC-1 and SRC-2 (TIF2/GRIP1)[6]. SRC interact not
only with nuclear receptors, such as estrogen receptor
(ER)[7], progesterone receptor
(PR)[7], and thyroid
receptor[5,8], but also with other transcription factors, including activator protein-1
(AP-1)[9], nuclear factor-kB
(NFkB)[10], signal transducer and activator of transcription
(STAT)[11] and E2F1[12]. Binding of SRC to
transcription factors will further recruit other chromatin modification factors, such as acetyltrans-ferases (CBP and p300) and
methyltransferases (CARM1 and PRMT1), modify the chromatin structure and activate transcription of their target
genes[13,14]. Thus, it is conceivable that changes of their concentrations and activities may greatly affect the expression levels of many
genes and, as a consequence, influence a variety of cellular processes.
Recently, SRC-3 has received more attention, because a growing body of evidence has revealed that overexpression of
SRC-3 might promote initiation and/or progression of carcinogenesis by affecting many important signal pathways. In this
review, we will focus on the involvement of SRC-3 in oncogenesis and discuss the potential mechanisms by which this
occurs.
Molecular structure of SRC-3
The SRC-3 gene encodes a 160 kDa coactivator, with 40% sequence similarity to other SRC family members. Furthermore,
SRC family members contain multiple similar functional domains (Figure 1). Their N-terminal basic
helix-loop-helix-Per/ARNT/Sim (bHLH-PAS) domain is the most conserved region among SRC family members (60% identity for amino acids
1-350)[1]. The bHLH-PAS domain can serve as DNA-binding, protein-protein interaction surfaces for various
bHLH-PAS-containing factors[15]. Actually, SRC family members have been shown to interact with myogenin, MEF-2C and
transcriptional enhancer factor (TEF) through this
domain[16,17]. It is also possible that this region could participate in intramolecular
interactions to regulate the activity of p160 coactivators or intermolecular interactions with other coactivators. One example
is coiled-coil coactivator (CoCoA), which binds the bHLH-PAS domain of SRC-2 and enhances ER-mediated
transcription[18].
The conserved central region of the SRC contains multiple LXXLL motifs (where L is leucine and X is any amino acid),
which interact with a hydrophobic cleft in the nuclear receptor LDB formed as a result of ligand-induced conformational
changes[19,20]. Two intrinsic transcriptional activation domains (AD1 and AD2) are located at the C-terminal of the receptor
interaction domain of the SRC molecules. The AD1 contains multiple LXXLL motifs that are responsible for interactions with
the histone acetyltransferase (HAT) CBP and p300. Although C-terminal domains of SRC-1 and SRC-3 possess HAT activity,
its HAT activities are weaker than those of CBP, p300 and
p/CAF[21]. Therefore, the importance of SRC HAT activity remains
unclear. AD2 can interact with protein arginine methyltransferases (PRMT), such as CARM1 and
PRMT1[22,23]. Based on the protein structure, it has been suggested that SRCs serve as adaptor proteins to recruit additional coactivators and basal
transcriptional machinery onto the promoter. Such recruitment may be critical for nuclear receptor-directed local chromatin
remodeling and assembly of the transcriptional machinery around the promoter.
SRC-3 in cancer
Clinical study SRC-3 is a steroid receptor coactivator, and SRC-3 amplification and/or overexpression is detected in many
hormone-sensitive tumors, such as breast, prostate, and ovarian cancer, and
meningioma[1,24-27]. In breast cancer biopsies,
SRC-3 was shown to be amplified and overexpress-ed in 5%-10% and 30%-60% of cases,
respectively[1,28]. In tamoxifen-treated breast cancer patients, SRC-3 overexpres-sion is associated with high levels of
HER-2/neu, tamoxifen resistance, and poor disease-free survival, suggesting that cross-talk between SRC-3, HER2/neu and ER signal pathways is important in
breast cancer[30,31]. In the case of prostate cancer, a study of SRC-3 expression in a series of 37 patients revealed that its
expression level correlated significantly with tumor grade and stage of
disease[24]. Further analysis of a cohort of 480 patients
with prostate cancer revealed that overexpression of SRC-3 was correlated with tumor recurrence and
survival[25]. Moreover, it has been reported that a splicing variant of SRC-3
(SRC-3-D3), encoding a 130 kDa protein that lacks the N-terminal bHLH
and a portion of the PAS domain, is overexpressed in breast cancer biopsies.
SRC-3-D3 is a highly potent steroid receptor coactivator
in vitro, even when present at a relatively low level, as compared with the full-length
SRC-3[32]. These data suggest that SRC-3 plays an essential role in hormone-sensitive tumors, probably by activating the activity of the steroid
receptor. Intriguingly, a recent study has revealed that SRC-3 overexpression is correlated with the absence of estrogen and
progesterone receptors in breast
cancer[29]. This suggests that SRC-3 may also function via other transcription factor(s)
during tumorigenesis.
Consistent with this finding, SRC-3 is also found to be involved in many types of non-steroid-targeted tumors, such as
pancreatic cancer, gastric cancer, colorectal carcinoma and hepatocellular carcinoma
(HCC)[33-37]. An increased number of SRC-3 gene copies were detected in 37% of pancreatic adenocarcinoma
cases[34]. Furthermore, progressive increased
frequency of SRC-3 expression was detected during pancreas cancer progression (the SRC-3 expression level follows the
following order: pancreatitis < low-grade pancreatic intraepithelial neoplasia [PanIN] < high-grade PanIN < invasive ductal
adenocarcinomas). Moreover, SRC-3 is also closely associated with metastasis and tumor recurrence in gastric
cancer[35] and HCC[37]. Taken together, these clinical data suggest that SRC-3 may play an important role in the genesis of human cancers
in a hormone-independent manner.
Lessons from mouse models
Transgenic mouse model To determine whether
SRC-3 is a bona fide oncogene, an SRC-3 transgenic mouse model was
generated by M Brown and
colleagues[38]. The over-expression of SRC-3, under the control of mouse mammary tumor virus
(MMTV) LTR in transgenic mice, was associated with an extremely high tumor incidence (76%) in aging animals, with an
average latency of 16 months. High tumor incidence was found in mammary glands (48/145 detected tumors), pituitary
(42/145), uterus (18/145) and lung (18/145), consistent with the high ectopic expression of SRC-3 in these
organs[38]. Further analysis revealed that the persistent hyperplastic lesions were caused by a combination of increased cellular proliferation
and reduced apoptosis. IGF-1, a growth factor important for cancer cell growth and survival, was induced at both the mRNA
and protein levels in normal mammary gland of SRC-3 transgenic mice. The serum level of IGF-1 was also elevated in
transgenic mice, suggesting that IGF-1 signaling is essential for SRC-3-induced tumorigenesis. Moreover, most of the
mammary tumors were invasive, and several adenocarcinomas were metastatic. Finally, the genesis of mammary tumors is
independent of the formation of pituitary adenomas, the reproductive history of the mice and the ER status, suggesting that
SRC-3 induced mammary tumors are not dependent on hormone level.
Because SRC-3-D3, a splicing variant of SRC-3, was
reported to be overexpressed in breast cancer specimens, overexpression of
SRC-3-D3, under the control of the cytome-galovirus (CMV) promoter in transgenic mice, was generated by AT Riegel and
colleagues[39]. Mammary epithelial cell
proliferation and ductal ectasia were found in
CMV-SRC-3-D3 mice, which is similar to the phenotype found in
MMTV-SRC-3 mice[38]. Moreover, both mouse models showed that prolactin, a hormone produced in the pituitary, was not related to
SRC-3- or SRC-3-D3-induced cell proliferation, which indicates that elevated hyperplasia is not related to prolactin. However, no
tumor was found in CMV-SRC-3-D3 animals, probably due to the lower transgene expression levels (no more than two-fold)
and the lack of elevated systemic IGF-1
levels[39]. These results indicate that both SRC-3 splicing variants are capable of
inducing mammary epithelial cell proliferation. Therefore, MMTV-SRC-3 transgenic mouse model provides evidence that
SRC-3 is an oncogene and that its overexpression is sufficient to trigger the initiation of tumorigenesis, which ultimately leads
to invasive carcinoma.
Knockout mouse model SRC-3 knockout mice have retarded growth, reduction in mammary gland alveolar
development during pregnancy, and resistance to growth hormones and
estrogen[40,41]. In addition, SRC-3 deficiency significantly
suppresses the incidence of MMTV-v-Ha-ras oncogene-induced mammary gland ductal hyperplasia,
tumorigenesis, and metastasis to the
lung[42]. Most SRC-3+/+-ras and
SRC-3+/--ras mice developed many mammary intraepithelial neoplasia lesions
by age 17 weeks. Fifty percent of the
SRC3+/+-ras mice (n=38) and
SRC3+/--ras mice (n=46) developed breast tumors by age
32.5 and 42 weeks, respectively. All of these mice developed palpable breast tumors by age 70 weeks. In comparison,
approximately 50% of the SRC-3-/--ras virgin mice still had normal mammary gland morphology by age 80 weeks. Significant
differences in mammary tumor incidence were also observed between
SRC-3+/+-ras and SRC-3-/--ras mice under different
hormonal conditions, suggesting that SRC-3-induced tumorigenesis is not likely through hormone regulated events.
Moreover, depletion of SRC-3 also significantly and selectively suppresses the mammary tumorigenesis induced by
chemical carcinogen 7,12-dimethylbenz[a]-anthracene (DMBA) with or without pituitary
isografts[43]. Mammary tumor incidence dropped from 45% and 44% in DMBA-treated
SRC-3+/+ and SRC-3+/- mice, respectively, to 11% in DMBA-treated
SRC-3-/- mice. Although skin tumors were also detected in these three groups, there were no significant differences in skin tumor
frequencies.
Molecular mechanisms of SRC-3 function
Hormone-dependent signal transduction
pathway Hormone modulation is closely related to tumorigenesis in breast,
ovarian and prostate cancer. SRC-3 is a member of the steroid receptor coactivator family and is necessary for the
complete functioning of ER[44,45]. Therefore, it is likely that
SRC-3 also plays an important role in estrogen-stimulated proliferation of
breast tumors. In line with this notion, suppression of SRC-3 leads to reduction of recruitment of
ERa and polymerase II to its target gene promoter, resulting in the inhibition of transcription. Interestingly, inhibition of SRC-3 protein expression has
a more detrimental effect on ERa target gene regulation than does inhibition of the other p160 protein,
SRC-1[46]. This result suggests possible coactivator specificity and SRC-3 may have more impact on ER activity than other members. Cyclin D1,
which is frequently overexpressed in tumors, is an
ERa target gene, and its expression is enhanced by SRC-3 through
functional interaction of the estrogen receptor with the cyclin D1
promoter[47]. SRC-3-D3, the splicing variant of SRC-3, can
increase the estrogenicity of a variety of natural and pharmacologic compounds in tissues that develop hormone-dependent
neoplasia. Thus, overexpression of SRC-3-D3 may be a contributing factor to the development of hormone-driven neoplasia
and to hormone resistant breast
cancers[48]. Taken together, these findings indicate that SRC-3 is required for maximal
activity of ER and other hormone receptors. Over-expression and/or amplification of SRC-3 is likely to facilitate
transformation by ER signaling in breast cancer.
Hormone-independent signal transduction pathway
SRC -3 abnormality has been detected in tumors that are not targeted by steroid hormones, such as gastric cancer and
HCC[35-37]. Overexpression of SRC-3 also exists in ER- or
PR-negative breast cancer[29]. This clinical evidence strongly supports the hypothesis that SRC-3 can enhance
hormone-independent proliferation and survival during tumorigenesis. Extensive investigations reveal that SRC-3 can interact with a
broad spectrum of transcription factors in addition to hormone
receptors[9-12]. Hence, many signal pathways, other than
hormone receptors, can be affected by overexpression of SRC-3 in cancer cells. Deregulation of this signaling will facilitate
tumorigenesis by altering cell differentiation, proliferation, survival and metastasis.
E2F1 signal pathway Regulation of cell cycle progression in mammalian cells is very complex, involving many signal
molecules. Among them, E2F1 transcription factor has been shown to regulate cell cycle progression by modulating the
expression of proteins required for the G1/S transition and DNA synthesis. In the G0 and early G1 phases, Rb binds to E2F1
and suppresses the transcriptional activity of E2F1. Phosphorylation of Rb family proteins by cyclin-
dependent kinase (CDK) results in the release of
E2F1[49]. The freed E2F1, which is present as a heterodimer with its
binding partner DP-1 or DP-2, is then activated and promotes the transcription of its target genes, such as cyclin A and
cyclin E. Because E2F1 is an important regulator of cell cycle progression, it is not surprising that transcription activity of
E2F1 is frequently induced in cancer cells. E2F4, another E2F family member, appears to function as a repressor by recruiting
Rb family proteins to E2F-regulated promoters. The repressor E2F4 is believed to be required for cell cycle exit and
differentiation[50].
Recently, SRC-3 has been found to directly interact with E2F1, but not with
E2F4[12]. The structural difference at the
N-terminal of E2F1 and E2F4 may account for this differential
binding[50]. The elevated expression of SRC-3 may expand the
available pool of the SRC-3-E2F1 complexes in quiescent cells to displace the repressive E2F complex from E2F1-
responsive promoters. Consequently, SRC-3-E2F1 trans-
activates the E2F1 target genes involved in cell proliferation. Those genes include cyclin E, Cdk2, cyclin A, cdc25A and E2F1
itself. Both E2F1 and cyclin E are potential proliferative markers, and are closely correlated with poor outcomes of breast
cancer[51-53]. Furthermore, ectopic expression of cyclin E in E2-responsive cells can effectively overcome the growth arrest
effected by antiestrogens[54]. Hence, SRC-3-induced E2F1 signaling may be an important mechanism for
hormone-independent breast cancer cell proliferation, as well as for other non-hormone dependent cancers.
Insulin-like growth factor-1/AKT signal pathway Insulin-like growth factor-1 (IGF-1)/AKT signaling has diverse roles
in cell processes such as cell growth, proliferation, survival, and
migration[55]. The binding of IGF-1 to its cognate receptor,
IGF1R, triggers phosphorylation of insulin receptor substrates (IRS-1 and IRS-2) and activation of phos-phatidylinositol
3-kinase (PI3K), which is followed by activation of AKT (Figure 2). Both
in vitro and in vivo data reveal that the SRC-3
expression level is closely and positively associated with the IGF-1 expression
level[38,40,41]. Moreover, the IGF1Ra protein
level is reduced in SRC-3 knockdown breast cancer cells, whereas
IGF1Ra is induced in CMV-SRC-3-D3 transgenic mice.
Furthermore, IGF1Ra is highly phosphorylated in tumors derived from MMTV-SRC-3 transgenic
mice[38,39,56]. Interestingly, no significant difference in
IGF1Rb was found, despite insulin response substrate-1 (IRS-1) and IRS-2 being dramatically
suppressed in SRC-3-/--Ras transgenic mice. As expected, IGF-1 downstream effector, AKT expression level and activity
become elevated on overexpression of SRC-3 in a prostate cancer cell
line[57]. Consistently, the activity of AKT is increased
in a MMTV-SRC-3 mouse model[38].
As a result, multiple downstream pathways of AKT
signaling are affected, mostly at the phosphorylation level. SRC-3 overexpression enhances somatic cell growth in prostate
cancer cells by activating AKT/mTOR
signaling[57]. In a MMTV-SRC-3 transgenic mice model,
GSK-3b, the substrate of AKT, is strongly phosphorylated at Ser 9, resulting in a reduced
b-catenin phosphorylation level (Ser 45). Unphos-phorylated
b-catenin will evade proteinase degradation and translocate into the nucleus, leading to the activation of target genes, such as
cyclin D1[38] (Figure 2). Collectively, the data above indicate that the expression level and/or activity of many components in
the IGF/AKT signaling are under the strict control of SRC-3.
NF-kB signal pathway Rel/Nuclear factor-kB
(NF-kB) is a dimeric transcription factor that plays important roles in the
control of growth, differentiation, and
apoptosis[58]. Rel/NF-kB consists of homodimers and heterodimers formed by several
subunits: NF-kB1 (p50/p105), NF-kB2 (p52/p100), RelA (p65), Rel B, and c-Rel proteins. The inactive form of
NF-kB is localized in the cytoplasm and consists of 3 subunits: the DNA-binding p50 and p65 subunits, and an inhibitory subunit,
called IkB, which is bound to p65. Once IkB is released through phosphorylation by
IkB kinase (IKK), NF-kB will translocate to the nucleus and bind to target sites on
DNA[58]. Activation of NF-kB results in the induction of a large number of genes
that influence cellular proliferation, inflammation, and cellular
adhesion[58]. Furthermore, aberrant
NF-kB activation has been implicated in the pathogenesis of several human malignancies, including cancer of the breast, prostate, gastrointestinal tract,
liver, pancreas and skin.
SRC-3 can interact and coactivate
p65/NFkB[59]. Recently, SRC-3, but not SRC-1, has been reported to associate with IKK,
suggesting the essential role of SRC-3 in the NF-kB signaling
pathway[60]. In response to tumor necrosis factor
(TNF)-a, SRC-3 is phosphorylated by the IKK complex. As a result, SRC-3 and
NFkB translocate from the cytosol to the nucleus. One
of the putative target genes of SRC-3, interleukin (IL)-6, which has an
NF-kB binding site in its promoter and plays an important role in tumor metastasis and
inflammation[61], is induced. Elevated IL-6 in both serum and prostate cancer tissues
acts as an autocrine growth factor in prostate cancer
progression[62,63]. Consistent with this notion, introduction of wild type
SRC-3 in SRC-3 null MEF cells can restore IL-6 induction by
TNF-a, but not SRC-3 phosphorylation
mutants[64]. This result indicates that phosphorylated SRC-3 is tightly linked to
NF-kB transcriptional activity. For a more detailed discussion of the
phosphorylation of SRC-3, readers are referred to a recent review by Wu
et al[65].
C/EBPb signal pathway The C/EBPb family of transcription factors has been implicated in the regulation of
proliferation and differentiation in the mammary gland and breast
carcinogenesis[66,67]. There are 2
C/EBPb isoforms: liver-enriched activating protein (LAP) and liver-enriched inhibitory protein (LIP). In comparison with LAP, LIP lacks the N-terminal
transactivation domain, but retains the dimerization and DNA-binding domain; therefore, it is thought that LIP functions as
a dominant negative C/EBPb isoform. In the mammary gland, increased LIP expression is associated with rapid mammary
epithelial cell proliferation during
pregnancy[66].
In CMV-SRC-3-D3 transgenic mice, there is a reduced
LAP/LIP ratio, due to the induction of LIP expression
levels[39]. Reduction of the LAP/LIP ratio by LIP overexpression in a mouse model can trigger hyperplasia in an ER-independent
manner, suggesting that an increase in LIP levels is related to mammary ductal hyperplasia in
CMV-SRC-3-D3 transgenic mice. However, so far little is known about how overexpres-sion of SRC-3 can preferentially induce LIP expression. Further
study is required to investigate whether SRC-3 induces LIP directly at the transcriptional level or at the translational level, and
whether SRC-3 can directly bind to the C/EBPb promoter.
HER2/neu/MAPK signal
pathway Although deregulated SRC-3 does not affect MAPK pathway activity in cells or in a
mouse model[43,57], SRC-3 serves as a conduit from
MAPK signaling to ER (Figure 2). MAPK can regulate
SRC-3 activity by phosphorylating SRC-3 and augment ER activity by increasing recruitment of p300 and associated histone acetyltransferase
activity[68]. Recently, a clinical study on breast cancer patients showed that SRC-3 and HER2/neu expression levels are
closely associated with the development of tamoxifen resistance, suggesting that the crosstalk between HER2/neu and
SRC-3 exists[30]. Further study indicated that tamoxifen recruits coactivator complexes to the ER-regulated pS2 gene promoter in
SRC-3 and HER2 over-expressing cells, whereas tamoxifen recruits corepressor complexes in SRC-3 overexpressing cells
without the overexpres-sion of HER2. It is proposed that the switch from corepressor complexes to coactivator complexes
might be the reason for the loss of tamoxifen
resistance[31]. Importantly, treatment with gefitinib, a factor inhibiting crosstalk
of EGFR and HER2 with ER, significantly restores tamoxifen抯 antagonistic effect on gene expression and anti-tumor function.
Concluding remarks and future
perspectives As illustrated above, more and more compelling evidence reveals that
SRC-3 is a bona fide oncogene. First of all, use of a MMTV-SRC-3 transgenic mouse model clearly indicates that full-length
SRC-3 is sufficient to initiate tumorigenesis. Furthermore, SRC-3 overexpression exists in a variety of cancer types and
integrates several vital signal pathways, such as nuclear receptor,
HER2/neu, IGF/AKT, and NFkB, which are frequently
deregulated in many cancers. These signal pathways are involved in cell proliferation, survival and migra-tion, suggesting
the central role of SRC-3 in tumorigenesis.
Reduction of SRC-3 in cancer cells by RNAi knockdown or ribozymes can markedly reduce tumor formation in nude
mice[25,45]; and a deficiency of SRC-3 in a mouse model can suppress tumorigenesis, when challenged with a carcinogen or the
oncogene H-ras[42,43]. Therefore, SRC-3
per se is a very attractive chemotherapeutic target.
However, there are still a number of important questions that remain to be addressed. Because of the role of SRC-3 in
carcinogenesis, it is worth asking how the activities of SRC-3 are modulated during carcinogenesis. Because elevated
SRC-3 can selectively activate one subset of nuclear receptors and transcription factors, such as E2F1, the selectivity of SRC-3
function in a cancer context can lead to the finding of new drug targets and novel therapeutic strategies. It has been
suggested that phosphorylated SRC-3 is associated with its oncogenic potential; thus, it might be important to evaluate
phosphorylated SRC-3 and/or investigate whether there are any activated mutations in SRC-3 in tumor biopsies. Recently
SRC-3 was found to physically interact with ER81, a PEA3 family member, and drive MMP-1 expression, which might be
involved in metastasis[69]. Thus, it is not unlikely that SRC-3 interacts with other transcription factors or even other proteins
unrelated to the transcription complex. Examination of the SRC-3 complex in a cancer context might enhance our
understanding of the role of SRC-3 in carcino-genesis.
Acknowledgement
We thank Dr Ray-chang WU and Dr Khoi CHU for their critical comments.
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