Open Journal of Urology, 2012, 2, 188-197 Published Online October 2012 (
The Role of Prolactin in the Evolution of Prostate Cancer
Maria Elena Hernandez1, Michael J. Wilson2
1Centro de Investigaciones Cerebrales and Facultad de Medicina, Universidad Veracruzana, Xalapa, Mexico
2Department of Pharmacology and Department of Laboratory Medicine and Pathology, University of Minnesota,
VA Medical Center, Minneapolis, USA
Received July 21, 2012; revised August 29, 2012; accepted September 21, 2012
Today there is significant information indicating an effect of prolactin on the prostate gland. It has been shown to be
involved in mechanisms leading to the synthesis of some proteins such as PSA and cathepsin D, synthesis of citrate and
accumulation of zinc. Also, at the behavioral level, prolactin is known to control some aspects of reproduction, includ-
ing documentation on the physiology of the prostate and the possibility to trigger pathologies in this sex gland. Al-
though the later still is not clear, there is a correlation between the level of prolactin and the presence of prostate pa-
thologies. Thus, the aim of this review is to show how prolactin is involved in the progression of some pathologies of
this male sexual gland.
Keywords: Second Messengers; Prolactin Receptor; Androgens; Hyperprolactinemia
1. Introduction
Prolactin (PRL) is a protein hormone that in vertebrates
regulates several functions, including those related to
glands involved in reproduction, such as the prostate. In
the latter, PRL controls the zinc uptake, citrate synthesis,
and the expression of both androgen receptor and cath-
epsin D. PRL also triggers pathologies in the prostate by
still unknown mechanisms. Notwithstanding the contro-
versy of whether it acts alone or in concert with andro-
gens, what is certain is that the serum elevation of PRL
has a significant relationship with the presence of hyper-
plasia or cancer of the prostate. However, to date there is
a poor interest on the issue since most of the information
suggests that androgens are the main hormone triggering
prostate cancer. Thus, this paper is focused to show that
PRL, alone or in combination with androgens, may also
be responsible for promoting the development of the di-
2. Prolactin in the Development and
Physiology of the Prostate Gland
PRL is a peptide hormone with a sequence of 199 ami-
noacids in humans and 197 in rats, with sequence simi-
larities to those of growth hormone (GH) and placental
lactogen (PL). These three hormones share geometric,
structural and biological characteristics; hence, they be-
long to the same family of proteins PRL/GH/PL [1]. Prl
has a molecular weight around 23 kDa, and is stabilized
by three disulfure links in residues of cysteine Cys4-Cys11,
Cys58-Cys174, and Cys191-Cys199, that form three loops
giving a particular shape to the molecule [2] Figure 1.
PRL is synthesized mainly in lactotroph cells (or mam-
motroph) in the adenohypophysis [3], and also by cells of
the mammary gland, uterus, and placenta [1]. Interest-
ingly PRL has also been reported present in the epithelial
cells of the prostate gland, suggesting a local impact on
the functioning of these cells [4]. It is also known that in
synergy with androgens, PRL controls the growth and
development of the prostate [5]. During normal devel-
opment PRL triggers duct morphogenesis, and in adults,
even in the absence of androgens, it induces the primary
growth of the stroma, a process also observed in trans-
genic mice with over expression of PRL [6]. On the other
hand, in rats it has been reported that PRL, along with
androgens, stimulates the development and secretory
activity of the prostate lobules, with the dorsal and lateral
regions most influenced by this synergism [7].
In adults, the main function of the prostate is to pro-
duce prostatic secretions, transferred to the urethra in
response to sexual stimulation for formation of the semen.
The content of this fluid is diverse, but only a few com-
ponents are under the control of PRL. Thus, it is known
that PRL stimulates the synthesis and/or accumulation of
citrate and zinc, and activation of Bcl-2 (antiapoptotic
protein) [8-14]. Also, it is reported that PRL stimulates
synthesis of certain proteins in a tissue-specific way; e.g.,
prostatein in the ventral prostate, probasin and the secre-
tory protein of the seminal vesicle (SVS-II or RWB) in
the dorsolateral prostate. Although little is known about
opyright © 2012 SciRes. OJU
Figure 1. Prolactin is a hormone secreted by the anterior
lobe of pituitary. In humans it is conformed for 199 amino-
acids with three disulfide bonds (Cys4-Cys11, Cys58-Cys174,
and Cys191-Cys199). Also this protein is produced by the
mammary gland, uterus, and placenta.
the function of these proteins, a relationship has been
observed between prostatein and mammary and prostatic
adenocarcinomas, and RWB with the sexual maturation
of the gland [13,15].
The prostate is an accessory sexual gland participating
in reproductive processes. It is known that following
sexual stimulation, there is an increase in the expression
levels of Cathepsin D, an enzyme synthetized by the
prostatic epithelial cells and integrated into the prostatic
secretion. The contact of a male with a female stimulates
the production of this enzyme, but the production is
greater if it is a non-contact stimulation [16]. Also in the
prostate, sexual stimulation triggers the increase of re-
ceptors for PRL and steroid hormones, specifically in-
creasing in expression of androgen receptors [17], the
long receptor to PRL [18], and the signal pathways of
STAT [19]. Although the relationship among these re-
sponding molecules is still unknown and the cell re-
sponses they evoke, it is clear that a sexual stimulus is
highly specific to promote the synthesis and release of
secretory components of the prostate needed for the se-
men to ensure survival of sperm, and in consequence,
ovum fertilization. Although there are few studies incur-
porating the effects of sexual stimulation, reducing the
number of PRL receptors does not affect the execution of
sexual behavior [20], but does alter fertility. Up to 20%
of subjects were able to induce pregnancy but can be-
come completely infertile with a longer time [5]. How-
ever, this is a topic that deserves further research.
3. Evidence of the Role of PRL in the
Development of Prostate Cancer
PRL is a hormone that participates in several functions in
vertebrates, one of them being the regulation of cell pro-
liferation. Therefore, many studies have focused on
evaluation of its role in the different pathologies that are
found in the prostate. An important feature of this gland
in men is a continuous growth throughout the life of the
subject. It has a slow and constant growth starting at the
age of 21 up to the age of 40. Then, there is a second
growth period triggered and the gland doubles its weight,
from 20 to 40 g, when the subject is around 80 years old.
However, in some situations of unknown etiology, this
growth is accelerated with the gland reaching a size and
weight above these normal levels; i.e., a weight of 50 to
80 g among men 40 and 50 years old, with different
problems associated with a prostate of this size. One of
them is benign prostatic hyperplasia (BPH; an enlarge-
ment produced by an increase in the number of cells) and
the other is a more aggressive phase, such as cancer. It is
largely unknown why and what is triggering this modifi-
cation, but it is known that PRL and testosterone, along
or together, seem to do something in the process [21-23].
It has been observed that some human subjects with
prostate pathologies have also a higher serum level of
PRL [24]. Although it is unknown whether PRL causes
the disease or the disease causes PRL increase, what is
known is that after inducing an increase in serum PRL,
the possibility of prostate pathology is significantly in-
creased [25]. Hence, PRL is now considered as a risk
factor in the etiology of prostate pathologies [26].
The idea is that PRL has something to do with prostate
pathologies was first demonstrated in several studies with
rodents. However, a conclusive demonstration has not
been easy to demonstrate due to experimental protocols
in use, as well as the possible role of androgens. In spite
of this, and with recent evidence, it has been found that
PRL can promote prostate cell growth [27,28] by acti-
vating a mechanism dealing with the inhibition of apop-
tosis. In the LNCaP cell line, as an example, this process
was observed when androgens were present [9,29]. Also,
it has been demonstrated that in synergy with androgens,
PRL can promote cell survival and differentiation, and in
the absence of androgens it increases the expression of
the short and long PRL receptors, and activates the
pathways of STAT and MAPK [4,30]. Prolactin has also
been proposed to induce nodular hyperplasia [31,32] and
dysplasia [13].
Studies from transgenic mice with an over expression
of the prostate PRL gene [31] and in ArKo mice (without
aromatase expression; [33], a dramatic enlargement of
the prostate associated with a decrease in the rate of
apoptosis and no disease was reported. The same effect
was shown in prostate cell cultures from the rat and hu-
man [30,34]. Thus, it has been proposed that a pathway
that seems to be independent from androgen actions
evokes PRL effects.
As can be appreciated, evaluation of PRL effects is not
an easy task because some pathologies require the pres-
ence of androgens, whereas others can be triggered just
in the presence of PRL. The questions raised are Why?
Copyright © 2012 SciRes. OJU
and How?. Although the answers are unknown, they
could be analyzed by the number and type of genes that
become activated by PRL to induce pathology, such as in
intraepithelial neoplasia [35]. However, there still is a
long way to go in order to decipher the mechanisms ac-
tivated by PRL that modify prostate morphogenesis.
4. Normal Pathways for PRL Signal
The pleiotropic function induced by PRL in different
tissues, including the prostate, starts with the link to a
specific membrane receptor, the prolactin receptor
(PRLR). It has been identified as a glucoprotein in sev-
eral tissues and species, and belongs to a superfamily of
receptors of the cytokine 1 type [5,36-38]. There is di-
versity in the isoforms of the receptor as a result of al-
ternative splicing of the RNA synthesized from a single
gene. The resulting receptors are different in length and
composition of their intracellular domain (DIC), but they
are similar in their extracellular (DEC) and transmem-
branal domains (DTM). In this sense, in humans 4 iso-
forms are described, a long one (L), a intermediate (I),
and two short (S1a and S1b); in the rat there are 3 iso-
forms, the L with 591 aa, I with 393 aa, and S with 291
aa; and in mice there are also 4 isoforms, the L (589 aa),
and three S (S1 with 291 aa, S2 with 284 aa; and S3 with
273 aa) [2,39,40] Figure 2.
The complex PRL-receptor (PRLR) can activate dif-
ferent pathways of intracellular signaling [41], including
Stat (signal transducers and activators of transcription
proteins). This group of proteins has 5 isoforms known
as Stat 1, Stat3, STAT5a and b, and Stat6 Figure 3. The
activation of each subunit is different depending on the
physiological stimulus. During sexual behavior it was
demonstrated that such stimulus induces modifications in
the level of activation of Stat1 and 3 in the prostate. The
level of activation of these 2 isoforms is increased with a
second consecutive ejaculation in rats, and response of
Stat3 was greater than Stat 1. Also, translocation of Stat3
protein to the nucleus was demonstrated, suggesting its
role in the regulation of genes probably related to the
synthesis of Cathepsin D [16,18], increased during sexual
behavior, and probably with regulation of those genes
related to cell proliferation.
The other groups of signal pathways used by PRL are
the mitogen-activated protein kinases (MAPK), also
known as ERK [42,43]. MAPK was the first group iden-
tified from all signal proteins, and is constituted of two
proteins with molecular weights of 44 and 42 kDa. The
two phosphoacceptor groups of Tyrosine and Threonine,
once phosphorylated, activate the MAPK [44,45]. How-
ever, both proteins have different functions, while ERK2
participates in cell proliferation, ERK1 regulates ERK2
negatively [46]. This signal pathway has a main function
in cell proliferation, but in the prostate it also regulates
survival, growth and apoptosis [47]. Although there are
several studies of ERK1/ERK2 in the prostate, to date it
is still unknown how they are related to the physiology
Figure 2. Different PRL receptor isoforms present in hu-
man, rat and mouse. There have been reported four iso-
forms in human; one long (L) one intermediate (I), and two
short (S1a and S2b). In rats, three isoforms: one long (L),
one intermediate (I), and one short (S). In mice, four: one
long (L) and three short (S1, S2, S3). All receptors remain
similar in their extracellular domain, the difference is in the
cytoplasmic domains of their longuitudes.
Figure 3. Major signaling pathways of PRLr activation.
After the union of PRL to its dimerized receptor, the PRLr
activates JAK proteins, these in turn phosphorylate STAT
that in consequence is dimerized and translocated to the
nucleus. The phosphorilated JAK2 can also activate the
MAPK signaling way throught of Fyn, SHC, GRB2 and
SOS molecules. The result of these two pathways is the ac-
tivation of some transcription factors (like c-Jun and c-Myc)
that promoute the expression of proliferation, differentation
and cell survival genes.
Copyright © 2012 SciRes. OJU
of the gland and their role when the gland is activated by
PRL. However, some studies from cell lines derived
from prostate cancer have shown that ERK regulates
proliferation, growth and cell survival when it is acti-
vated by growth factors or even androgens [47]. On the
contrary, it was shown that PRL is unable to activate this
pathway when it is added to organ culture [8].
Another group of signal pathways used by PRL to in-
duce effects on prostate epithelial cells is the JNK/SAPK
[48]. These kinases have a molecular weight of 54 kDa
[44], which, similar to the ERK 1 and 2, requires the
phosphorylation at Threonine and Tyrosine sites to be-
come activated. They respond to several stimuli such as
UV light, X-rays, hydrogen peroxide, and some hor-
mones including interleukine 1-β (1L-1β), growth factors,
and PRL [45,49]. These kinases participate in different
functions such as proliferation, oncogenetic transforma-
tion, differentiation, inflammation, development, and
apoptosis [50]. However, in the specific case of prostate
cells, it was observed that following activation of this
pathway by PRL, growth could be the result of inhibition
of cell apoptosis, with few effects on cell proliferation.
This suggests that PRL promotes the survival of PC3 and
DU145 cells, instead of promoting cell proliferation
when this signal pathway is activated [51]. There is suf-
ficient information showing that these signal pathways
become active during prostate pathologies, although
there are few studies making a correlation of these path-
ways with PRL effects. Hence, to date it is still unknown
which proteins and genes are activated for the induction
of prostate pathologies by PRL, neither is it known what
occurs in subjects with sexual experience.
5. Alterations in PRL Signal Transduction to
Induce Progression of Prostate Cancer
Now it is clear that PRL regulates the prostate by pro-
moting the synthesis of semen components, and influ-
ences the expression of some genes by itself or along
with androgens. However, its function seems to be dual
because it also can modify the prostate in its physiology
and morphology in such a way that leads to several kinds
of disease states [9,52]. The mechanisms to trigger those
events can be diverse, but briefly they can be summed in
three steps: the first includes the elevation of systemic
levels of PRL, the second is in relation to a higher den-
sity of its receptors, and the third is related to the altera-
tion in the signal pathways activated following PRL
stimulation. The sum of all of them will finally generate
prostate pathologies.
In humans, hyperprolactinemia (HyperPRL) caused by
a prolactinoma or any other disorder in the hypophyseal
system, is one of the most frequent pituitary clinical dis-
eases. In the short term, the frequent effects of hyperPRL
in males are infertility, low sexual desire, and sexual
impotence; while in the long term it can generate prostate
diseases. Although the latter effect is not conclusive at all,
there is a high correlation between HyperPRL and pros-
tate diseases [53]. No matter that controversy exist
whether PRL triggers prostate diseases, a fact is that this
sex gland has receptors for this hormone that promote
proliferation once activated by PRL [54]. What are the
mechanisms to trigger those effects? To date they are not
known, but it has been shown that one of them includes
receptor modulation, that is, the receptor affinity changes
as a consequence of the increase in PRL levels [55]. Such
change is due to the modification of the lipidic flux,
which makes the receptor to be oriented in such a way
that increases its probability to receive the hormone [56].
Also, another mechanism proposed is a higher expression
of a single receptor type [54]. This was also observed in
our lab, the expression of the short receptor was in-
creased after short treatments of hyper PRL for 15 days
of hyperPRL [57]. Modulating receptor expression is not
just a response to serum levels of PRL but also the de-
gree of the disease, that is, an increase in the expression
of PRL receptors has been found in dysplastic tissue, but
reduced in a more malignant tissue. This suggests that
PRL plays an important role in the induction, develop-
ment and maintenance of the malignant stage and par-
ticipates in the early neoplasic transformation, but not in
more developed stages [42].
In the case of signal pathway variations observed in
the expression of different STAT isoforms, the individual
forms were dependent on the actual pathology of the
prostate. STAT3, for example, was found to increase in
the cell line LNCaP [58,59], and also during the trans-
formation process leading to the refractory prostate can-
cer [60]. Also, STAT3 is continuously active in the epi-
thelium of malignant prostates and this activation has
been associated with advanced cancer. In those subjects
with metastasis, STAT3 is 67% more active with a direct
correlation with the serum levels of PSA and with the
degree of the pathology according with the Gleason scale
[61]. On the other hand, in DU145 and PC-3 cells, it was
shown that STAT3 promotes cell migration because it
induces the formation of lamelipodia as a consequence of
the rearrangement of actin and microtubules [62]. Acti-
vation of STAT 5 a/b was observed in the induction of
histological changes, and a transcriptional modification
in STAT 5a/b is necessary in order to promote develop-
ment of cancer, that is, expression of a truncated form at
the amino terminal of this isoform avoids the repressive
action of the inhibitory protein PIAS3 (protein inhibitor
of activated STAT) and allowing increased cell prolifera-
tion [63]. Also, increased activation of the MAP kinase
pathway is found in prostate diseases. In prostate tissue
samples with hyperplasia, intraepithelial neoplasia or
Copyright © 2012 SciRes. OJU
Copyright © 2012 SciRes. OJU
undifferentiated tumors, a strong activation of the MAP
p38 is observed, but such activation is not observed in
those tumors with some differentiation. Likewise it was
shown that inhibition of this pathway could slow down
proliferation of PC3 cells [47]. Finally, there is also evi-
dence indicating that the PI3/AKT pathway is implicated
in pathologies of the prostate, as this pathway is highly
active in LNCaP cells from human carcinoma [64]. The
question is: how are these pathways related to PRL for
triggering prostate diseases? The few data in this regard
indicate that PRL can maintain the activation of these
proteins in epithelial cells and by this means promote
proliferation and survival of cells in the hyperplastic and
cancer tissues [38,47,65]. In other words, activation by
PRL of the STAT 5 a/b pathway via Janus Kinase-2
promotes development of cell proliferation, because its
inhibition makes the cells enter apoptosis [63], and ap-
parently MAPK does not seem to participate in this
process [8].
6. Alterations in Transduction Pathways of
PRL. Relationship with the Androgen
As far as can be determined, hyperprolactinemia alters
prostate morphology and the extent of these effects differ
depending on the degree and duration of elevated PRL
exposure [66]. The mechanisms for this could include
changes at the PRL receptor level and signal pathways,
but also they could be related to the androgen receptor.
The prostate is highly dependent on androgens to or-
chestrate its appropriate functions, and involution of the
gland occurs when this steroid is absent. In vitro studies
have shown that decrease in the expression of PIAS1 and
SRC1 in hormone-refractory tumors alters the transcrip-
tional activity of the AR, suggesting that these cofactors
could be involved in the progression of prostate cancer
[67,68]. Likewise, diverse mutations in the AR could be
another mechanism that lead to or maintains the growth
of prostate tumors [69]. However, it is also known that
the effects could be mediated together with other hor-
mones such as PRL, which is known to be able to alter
the morphology of the prostate Figure 4. Thus, regula-
tion of prostate pathologies seems to rely on complex
events that include at least both of these hormones.
It was observed that hyperprolactinemia, induced by
an implant of hypophyseal tissue, produces an increase in
the weight and DNA content of the lateral lobule of the
prostate and a higher concentration of AR in the nucleus.
Since hyperprolactinemia produces a decrease in the
concentration of testosterone in blood [9,70], it was pro-
posed that PRL can promote the growth of this lobule by
increasing the density of the nuclear AR and by this
Figure 4. Image of the ventral and dorsolateral prostate tissue. Subjects were treated with prolactin for 3 months. Panel A
and B represents normal tissue of the ventral and dorsolateral prostate, showing epithelial cells with typical columnar and
cuboidal shape, respectively. Panels C and D represent a ventral and dorsolateral tissue treated with prolactin. Under this
condition ephitelial cells completely lose columnar and cuboidal shape, and the cells are invading the lumen as a result of cell
proliferation (arrow). L = lumen, Bar = 50 µm.
mean optimize the response to circulating androgens [15].
However, the increase of both its protein and its messenger
RNA, can be decreased as a consequence of the perma-
nent activation of the Ras-Erk pathway [71]. Also, an
increase in AR concentration was observed in hyper-
prolactinemic subjects that do not show the aromatase
enzyme. Under these conditions, an enlargement of the
gland was found with some hyperplasic areas [33]. The
effects genererted by PRL and AR are not only related to
activation of the MAPK pathway but also to that of
STAT, which also seems to be implicated. An associa-
tion between the AR and STAT at the nucleus level was
reported and it was proposed that it could be another
mechanism for PRL to induce cell proliferation in the
prostate [43,72].
The pathological effects of androgens and prolactin
also seem to be mediated via activation of the c-myc
protein (Figure 3), that has a role in cellular proliferation
and apoptosis [73]. In physiological conditions it was
reported low levels of this protein but in pathological
conditions there is an increase. Thus, in the hyperplasic
prostate gland of humans it is found high levels of c-myc,
and it also occurs in the intraepithelial neoplasias and
cancer, with the effect seen mainly at the nucleus level
[74], where a high rate of gene transcription is observed
as a consequence of the acetylation increase [75]. On the
other hand, it has been reported a stepwise increase of
this protein, from the normal tissue to a low and high
intraepithelial neoplasia [74]. The increase in the patho-
logical tissue is by activation of the PI3/Akt and MAPK
pathways and both of them may act in concert to upregu-
late the c-myc [76,77]. The overexpression of c-myc in
prostate cancer also seems to result from a downregula-
tion of a set of microRNAs such as miR-34a [78,79], or
because of a decrease in androgen actions through the
let-7c microRNA [80]. Furthermore, it has been shown
an over expression of c-myc induced by PRL in lym-
phoma cells through activating the cascade PI3/Akt [48].
In conclusion, to date, the existing information on how
PRL can induce prostate pathologies is far from being
conclusive. However, what we have observed at this time
is that, along with aging of the subject, serum levels of
PRL are increased while those of testosterone are de-
creased, and this hormonal imbalance can be the appro-
priate means to trigger prostate pathologies, induced
mainly by PRL. In other words, the rise of PRL during
aging is the key for the presence of prostate pathologies.
The question raised is: how does PRL trigger the pa-
thologies? The response is still unknown and neither can
it be explained by only the increase in the density of its
receptors or by the activation of signal pathways, because
the latter are poorly convincing. A second question that
we must keep on mind is: is it important to know whether
the signal pathways are activated (transient or continuous
activation; rapid turnover versus extended binding of
PRL by its receptors) or it better expected that prolonged
activation of involved pathways leads to activation of
additional genes with changes in tissue characteristics
and development of pathology? No matter the techno-
logical advances and the tools existing today, it is still a
difficult issue to deal with these questions, but not im-
possible. We just require the sum of efforts to understand
the generation of this kind of disease.
The mechanisms used by PRL to induce prostate pa-
thologies seem to be quite varied, but the information
obtained to date suggests that this hormone can induce
prostate pathologies and proliferation via PI3/Akt and
MAPK pathways activation, by overexpression of c-myc,
as well as by inhibition or activation of some micro-
RNAs such as the miR-341a and let-7c. However, it still
remains to analyze how they are related in order to pro-
mote cellular migration and also how these proteins af-
fect the cytoskeleton, that is necessary not only to main-
tain cellular form but also required to maintain the cell
attached to the extracellular matrix; questions that are
just started to be addressed.
7. Acknowledgements
Supported by sabbatical fellowship 159818, CONACyT
grant 106531, Department of Veterans Affairs (MW) and
program of academic collaboration. We thank the tech-
nical assistance of Daisy Herrera and Cynthia Fernandez.
[1] A. Bachelot and N. Binart, “Reproductive Role of Prolac-
tin,” Reproduction, Vol. 133, No. 2, 2007, pp. 361-369.
[2] N. Ben-Jonathan, C. R. LaPensee and E. W. LaPensee,
“What Can We Learn From Rodents about Prolactin in
Humans?” Endocrine Review, Vol. 29, No. 1, 2008, pp.
1-41. doi:10.1210/er.2007-0017
[3] J. Neil and G. Nagy, “Prolactin Secretion and Its Con-
trol,” In: E. Knobil and J. D. Neill, Eds., The Physiology
of Reproduction, Raven Press, New York, 1994, pp.
[4] M. T. Nevalainen, E. M. Valve, P. M. Ingleton, M. Nurmi,
P. M. Martikainen and P. L. Harkonen, “Prolactin and
Prolactin Receptors Are Expressed in Human Prostate,”
The Journal of Clinical Investigation, Vol. 99, No. 4,
1997, pp. 618-627. doi:10.1172/JCI119204
[5] C. Boyle-Feysot, V. Goffin, M. Edery, N. Binart and P.
Kelly, “Prolactin and Its Receptors: Actions, Signal
Transduction Pathways and Phenotypes Observed in PRL
Receptor Knockout Mice,” Endocrine Review, Vol. 19,
No. 3, 1998, pp. 225-2268. doi:10.1210/er.19.3.225
[6] J. Kindblom, K. Dillner, L. Sahlin, F. Robertson, C. Or-
mandy, J. Törnell and H. Wennbo “Prostate Hyperplasia
Copyright © 2012 SciRes. OJU
in a Transgenic Mouse with Prostate-Specific Expresion
of Prolactin,” Endocrinology, Vol. 144, No. 6, 2003, pp.
2269-2278. doi:10.1210/en.2002-0187
[7] C. Nicoll, “Physiological Actions of Prolactin,” In: J.
Field, H. Magoun and V. Hall, Eds., Handbook of Phy-
siology. A Critical, Comprehensive Presentation of Phy-
siological Knowledge and Concepts, American Physio-
logical Society, 1994, pp. 263-264.
[8] T. J. Ahonen, P. L. Härkönen, H. Rui and M. T.
Nevalainen, “PRL Signal Transduction in the Epithelial
Compartment of Rat Prostate Maintained as Long-Term
Organ Cultures in Vitro,” Endocrinology, Vol. 143, No. 1,
2002, pp. 228-238. doi:10.1210/en.143.1.228
[9] F. Van Coppenolle, C. Slomianny, F. Carpentier, B. Le, A.
Ahidouch, D. Croix, G. Legrand, F. Dewailly, S. Fornier,
H. Caouss, D. Authie, J. Raynaud, C. Beauvillain, P. Du-
pouy and N. Prevarskaya, “Effects of Hyperprolactine-
mia on Rat Prostate Growth: Evidence of Androgen-De-
pendence,” American Journal of Physiology Endocrino-
logy and Metabolism, Vol. 280, No. 1, 2001, pp. E120-
[10] L. C. Costello, Y. Liu, J. Zou and R. B. Franklin, “Evi-
dence for a Zinc Uptake Transporter in Human Préstate
Cancer Cells Which Is Regulated by Prolactin and Tes-
tosterone,” Journal of Biological Chemestry, Vol. 274,
No. 25, 1999, p. 504. doi:10.1074/jbc.274.25.17499
[11] L. C. Costello and R. B. Franklin, “Effect of Prolactin on
the Prostate,” Prostate, Vol. 24, No. 3, 1994, pp. 162-
166. doi:10.1002/pros.2990240311
[12] L. C. Costello, L. Lao and R. Franklin, “Citrate Modula-
tion of High-Affinity Aspartate Transport in Prostate
Epithelial Cells,” Cellular and Molecular Biology, Vol.
39, No. 5, 1993, pp. 515-524.
[13] E. Reiter, B. Hennuy, M. Bruyninx, A. Cornet, M. Klung,
M. McNamara, J. Closset and G. Hennen, “Effects of Pi-
tuitary Hormones on the Prostate,” Prostate, Vol. 38, No.
2, 1999, pp. 159-165.
[14] J. Kindblom, “Actions of Prolactin in the Prostate Gland,”
In: D. Hoseman, Ed., Prolactin, Kluwer Academic Pub-
lishers Inc., New York, 2001, pp. 233-245.
[15] G. S. Prins and C. Lee, “Biphasic Response of the Rat
Lateral Prostate to Increasing Level of Serum Prolactin,”
Biology of Reproduction, Vol. 29, No. 4, 1983, pp. 938-
945. doi:10.1095/biolreprod29.4.938
[16] R. Diaz, “Niveles de Catepsina D Prostática en Respuesta
a la Estimulación Sexual en Ratas” Ph.D. Thesis, Uni-
versidad Veracruzana, Veracruz, 2006.
[17] M. E. Hernández, A. Soto-Cid, G. E. Aranda-Abreu, R.
Díaz, F. Rojas, L. I. Garcia, R. Toledo and J. Manzo, “A
Study of the Prostate, Androgens and Sexual Activity of
Ale Rats,” Reproductive Biology and Endocrinology, Vol.
16, No. 5, 2007, pp. 11-19. doi:10.1186/1477-7827-5-11
[18] M. Silva, “Niveles de mRNA del Receptor a Prolactina en
la Próstata Durante la Conducta Sexual de la Rata,” Ph.D.
Thesis, Universidad Veracruzana, Veracruz, 2009.
[19] A. Soto-Cid, C. R. Hernandez-Kelly, M. E. Hernandez, J.
Manzo, E. González-Mejia, R. C. Zepeda and A. Ortega,
“Signal Transducers and Activators of Transcription 1
and 3 in Prostate: Effect of Sexual Activity,” Life Sci-
ences, Vol. 79, No. 9, 2006, pp. 919-924.
[20] N. Binart, N. Melaine, C. Pineau, H. Kercret, A. M.
Touzalin, P. Imbert-Bolloré, P. A. Kelly and B. Jégou,
“Male Reproductive Function Is Not Affected in Prolactin
Receptor-Deficient Mice,” Endocrinology, Vol. 144, No.
9, 2003, pp. 3779-3782. doi:10.1210/en.2003-0409
[21] S. Odoma, G. D. Chisholm, K. Nicol and F. K. Habib,
“Evidence for the Association between Blood Prolactin
and Androgen Receptors in BPH,” Journal of Urology,
Vol. 133, No. 4, 1985, pp. 717-720.
[22] J. Meng, C. H. Tsai-Morris and M. L. Dufau, “Human
Prolactin Receptor Variants in Breast Cancer: Low Ratio
of Short Forms to the Long-Form Human Prolactin Re-
ceptor Associated with Mammary Carcinoma,” Cancer
Research, Vol. 64, No. 16, 2004, pp. 5677-5682.
[23] S. K. Peirce and W. Y. Chen, “Quantification of Prolactin
Receptor mRNA in Multiple Human Tissues and Cancer
Cell Lines by Real Time RT-PCR,” Journal of Endocri-
nology, Vol. 171, No. 1, 2001, pp. R1-R4.
[24] P. Lissoni, M. Mandala, F. Ropvelli, M. Casu, F. Rocco,
G. Tancini and E. Scardino, “Paradoxical Stimulation of
Prolactin Secretion by L-Dopa in Metastatico Prostate
Cancer and Its Possible Role in Prostate-Cancer-Related
Hyperprolactinemia,” European Urology, Vol. 37, No. 5,
2000, pp. 569-572. doi:10.1159/000020194
[25] A. Negro-Vilar, W. A. Saad and S. M. McCann, “Evi-
dence for a Role of Prolactin in Prostate and Seminal
Vesicle Growth in Immature Male Rats,” Endocrinology,
Vol. 100, No. 3, 1977, pp. 729-737.
[26] P. W. Harvey, D. J. Everett and C. J. Springall, “Adverse
Effects of Prolactin in Rodents and Humans: Breast and
Prostate Cancer,” Journal of Psichopharmacology, Vol.
22, No. 2, 2008, pp. 20-27.
[27] Y. de Launoit, R. Kiss, V. Jossa, M. Coibion, R. J. Pari-
daens, E. De Backer, A. J. Danguy and J. L. Pasteels, “In-
fluences of Dihydrotestosterone, Testosterone, Estradiol,
Progesterne, or Prolactin on the Cell Kinetics of Human
Hyperprolastic Prostatic Tissue in Organ Culture,” Pros-
tate, Vol. 13, No. 2, 1988, pp. 143-153.
[28] L. Romero, C. Muñoz, A. López and J. Vilches, “Relation
of Prolactin with Nodular Hyperplasia and Carcinoma of
the Prostate,” Actas Urologicas Españolas, Vol. 15, No. 6,
1991, pp. 503-509.
[29] D. Giuffrida, A. Perdichizzi, M. C. Giuffrida, S. La Vi-
gnera, R. D’Agata, E. Vicari and A. E. Calogero, “Does
Prolactin Induce Apoptosis? Evidences in a Prostate
Cancer in Vitro Model,” Journal of Endocrinological In-
vestigation, Vol. 33, No. 5, 2010, pp. 313-317.
[30] T. J. Ahonen, P. L. Härkönen, J. Laine, H. Rui, P. M.
Martikainen and M. T. Nevalainen, “Prolactin Is a Sur-
Copyright © 2012 SciRes. OJU
vival Factor for Androgen-Deprived Rat Dorsal and
Préstate Epithelium in Organ Culture,” Endocrinology,
Vol. 140, No. 11, 1999, pp. 5412-5421.
[31] K. Dillner, J. Kindblom, A. Flores-Morales, R. Shao, J.
Törnell, G. Norstedt and H. Wennbo, “Gene Expression
Analysis of Prostate Hyperplasia in Mice Overexpressing
the Prolactin Gene Specifically in the Prostate,” Endo-
crinology, Vol. 144, No. 11, 2003, pp. 4955-4966.
[32] A. Colao, G. Vitale, A. Di Sarno, S. Spiezia, E. Guerra, A.
Ciccarelli and A. Lombardi, “Prolactin and Prostate Hy-
pertrophy: A Pilot Observational, Prospective, Case-
Control Study in Men with Prolactinoma,” Journal of
Clinical Endocrinology and Metabolism, Vol. 89, No. 6,
2004, pp. 2770-2775. doi:10.1210/jc.2003-032055
[33] S. J. McPherson, H. Wang, M. E. Jones, J. Pedersen, T. P.
Lismaa, N. Wreford, E. R. Simpson and G. P. Risbridger,
“Elevated Androgens and Prolactin in Aromatesa-De-
fiicient Mice Cause Enlargement, But Not Malignancy, of
the Prostate Gland,” Endocrinology, Vol. 142, No. 6,
2001, pp. 2458-2467. doi:10.1210/en.142.6.2458
[34] A. Ruffion, K. A. Al-Sakkaf, B. L. Brown, C. L. Eaton, F.
C. Hamdy and P. R. Dobson, “The Survival Effect of
Prolactin on PC3 Prostate Cancer Cells,” European Uro-
logy, Vol. 43, No. 3, 2003, pp. 301-308.
[35] N. N. Tam, C. Y. Szeto, J. M. Freudenberg, A. N.
Fullenkamp, M. Medvedovic and S. M. Ho, “Research
Resource: Estrogen-Driven Prolactin-Mediated Gene-Ex-
pression Networks in Hormone-Induced Prostatic Intra-
epithelial Neoplasia,” Molecular Endocrinology, Vol. 24,
No. 11, 2010, pp. 2207-2217. doi:10.1210/me.2010-0179
[36] Z. Z. Hu, “Study of the Interrelationship of Prolactin Se-
cretion, Thyroid and Ovarian Function,” Zhonghua Fu
Chan Ke Za Zhi, Vol. 19, No. 4, 1984, pp. 210-214.
[37] A. Ouhtit, G. Morel G and P. A. Kelly, “Visualization of
Gene Expression of Short and Long Forms of Prolactin
Receptor in Rat Reproductive Tissues,” Biology of Re-
production, Vol. 49, No. 3, 1993, pp. 528-536.
[38] J. Rillema, “Prolactin Actions. Encyclopedia of Repro-
duction,” Academic Press, New York, 1999.
[39] M. E. Freeman, B. Kanyicska, A. Lerant and G. Nagy,
“Prolactin: Structure, Function, and Regulation of Se-
cretion,” Physiological Review, Vol. 80, No. 4, 2000, pp.
[40] J. Harris, P. M. Stanford, S. R. Oakes and C. J. Ormandy,
“Prolactin and the Prolactin Receptor: New Targets of an
Old Hormone,” Annals of Medicine, Vol. 36, No. 6, 2004,
pp. 414-425. doi:10.1080/07853890410033892
[41] P. A. Kelly, N. Binart, M. Freemark, B. Lucas, V. Goffin
and B. Bouchard, “Prolactin Receptor Signal Transduc-
tion Pathways and Actions Determined in Prolactin Re-
ceptor Knockout Mice,” Biochemical Society Transac-
tions, Vol. 29, No. 2, 2001, pp. 48-52.
[42] I. Leav, F. B. Merk, K. F. Lee, M. Loda, M. Mandoki, J.
E. McNeal and S. Ho, “Prolactin Receptor Expression in
the Developing Human Prostate and in Hyperplastic,
Dysplastic, and Neoplastic Lesions,” American Journal of
Pathology, Vol. 154, No. 3, 1999, pp. 863-870.
[43] B. Lewis, “Traducción de Señales,” Oxford University
Press, Oxford, 2001.
[44] G. Pearson, J. M. English, M. A. White and M. H. Cobb,
“ERK5 and ERK2 Cooperate to Regulate NF-kappaB and
Cell Transformation,” Journal of Biological Chemistry,
Vol. 276, No. 11, 2001, pp. 7927-7931.
[45] G. Pearson, F. Robinson, G. T. Beers, B. E. Xu, M.
Karandikar, K. Berman and M. H. Cobb, “Mitogen-Ac-
tivated Protein (MAP) Kinase Pathways: Regulation and
Physiological Functions,” Endocrine Reviews, Vol. 22,
No. 2, 2001b, pp. 153-183. doi:10.1210/er.22.2.153
[46] R. Lefloch, J. Pouyssegur and P. Lenormand, “Single and
Combined Silencing of ERK1 and ERK2 Reveals Their
Positive Contribution to Growth Signaling Depending on
Their Expression Levels,” Molecular Cell Biology, Vol.
28, No. 1, 2008, pp. 511-527.
[47] P. D. Maroni, S. Koul, R. B. Meacham and H. K. Koul,
“Mitogen Activated Protein Kinase Signal Transduction
Pathways in the Prostate,” Cell Communication and Sig-
naling, Vol. 2, No. 1, 2004, pp. 114-123.
[48] M. A. Dominguez-Caceres, J. M. Garcia-Martinez, A.
Calcabrini, L. Gonzalez, P. G. Porque, J. Leon and J.
Martin-Perez, “Prolactin Induces c-Myc Expression and
Cell Survival through Activation of Src/Akt Pathway in
Lymphoid Cells,” Oncogene, Vol. 23, No. 44, 2004, pp.
7378-7390. doi:10.1038/sj.onc.1208002
[49] J. Aguilera, “Comunicación Intra e Intercellular,” In: M.
E. Hernández and A. Ortega, Eds., Fisiología Celular y
Molecular: Principios y Conceptos, Universidad Vera-
cruzana, Veracruz, 2004, pp. 97-112.
[50] K. L. Schwertfeger, S. Hunter, L. E. Heasley, V. Levresse,
R. P. Leon, J. DeGregori and S. M. Anderson, “Prolactin
Stimulates Activation of c-jun N-Terminal Kinase (JNK),”
Molecular Endocrinology, Vol. 14, No. 10, 2000, pp.
1592-1602. doi:10.1210/me.14.10.1592
[51] A. Rufion, E. Fontaine and F. Staerman, “Hormonal
Therapy in Metastatic Cancer,” Progress in Urology, Vol.
13, No. 2, 2003, pp. 334-341.
[52] L. Tangbanluekal and C. L. Robinette, “Prolactin Medi-
ates Estradiol-Induced Inflammation in the Lateral Pros-
tate of Wistar Rats,” Endocrinology, Vol. 132, No. 6,
1993, pp. 2407-2416. doi:10.1210/en.132.6.2407
[53] K. Berinder, O. Akre, F, Granath and A. L. Hulting,
“Cancer Risk in Hyperprolactinemia Patines: A Popula-
tion-Based Cohort Study,” European Journal of Endo-
crinology, Vol. 165, No. 2, 2011, pp. 209-215.
[54] J. F. Sissom, M. L. Eigenbrodt and J. C. Porter, “Anti-
Growth Action on Mause Mammary and Prostate Glands
of Monoclonal Antibody to Prolactin Receptor,” Ameri-
can Journal of Pathology, Vol. 133, No. 3, 1988, pp.
Copyright © 2012 SciRes. OJU
[55] M. Ben-David, T. Kadar and A. V. Schally, “Micro-
method for the Determination of Free and Total Prolactin
Receptors: Measurement of Receptor Levels in Normal
and Malignant Mammary and Prostate Tissues,” Pro-
ceedings of the National Academy of Sciences, Vol. 83,
No. 21, 1986, pp. 8375-8379.
[56] J. R. Dave and R. J. Witorsch, “Prolactin Increases Lipid
Fluidity and Prolactin Binding of Rat Prostatic Mem-
branes,” American Journal of Physiology, Vol. 248, No. 6,
1985, pp. E687-E693.
[57] P. Mathey, “Efecto de la Hyperprolactinemia Sobre los
Niveles de Expresión del RNA Mensajero Para el Recep-
tor a Prolactina y vías de Señalización en la Próstata,”
Ph.D. Thesis, Universidad Veracruzana, México, 2011.
[58] W. Lou, Z. Ni, K. Dyer, D. J. Tweardy and A. C. Gao,
“Interleukin-6 Induces Prostate Cancer Cell Growth Ac-
companied by Activation of State Signaling Pathway,”
Prostate, Vol. 42, No. 3, 2000, pp. 239-242.
[59] M. T. Spiotto and T. D. Chung, “STAT3 Mediates
IL-6-Induced Growth Inhibitionin the Human Prostate
Cancer Cell Line LNCaP,” Prostate, Vol. 42, No. 2, 2000,
pp. 88-98.
[60] L. Tam, L. M. McGlynn, P. Traynor, R. Mukherjee, J. M.
S. Bartlett and J. Edwards, “Expression Levels of the
JAK/STAT Pathway in the Transition from Hormone-
Sensitive to Hormone-Refractory Prostate Cancer,” Bri-
tish Journal of Cancer, Vol. 97, No. 7, 2007, pp. 378-
383. doi:10.1038/sj.bjc.6603871
[61] J. Abdulghani, L. Gu, A. Dagvadorj, J. Lutz, B. Leiby, G.
Bonuccelli, M. P. Lisanti, T. Zellweger, K. Alanen, T.
Mirtti, T. Visakorpi, L. Bubendorf and M. T. Nevalainen,
“Stat3 Promotes Metastatic Progression of Prostate Can-
cer,” American Journal of Pathology, Vol. 172, No. 6,
2008, pp. 1717-1728. doi:10.2353/ajpath.2008.071054
[62] X. Liu, Z. He, C. H. Li, G. Huang, C. Ding and H. Liu,
“Correlation Analysis of JAK-STAT Pathway Compo-
nents on Prognosis of Patients with Prostate Cancer,” Pa-
thology Oncology Research, Vol. 18, No. 1, 2012, pp. 17-
23. doi:10.1007/s12253-011-9410-y
[63] A. Dagvadorj, S. H. Tan, Z. Liao, J. Xie, M. Nurmi, K.
Alanen, H. Rui, T. Mirtti and M. T. Nevalainen, “N-
Terminal Truncation of Stat5a/b Circumvents PIAS3-
Mediated Transcriptional Inhibition of Stat5 in Prostate
Cancer Cells,” International Journal of Biochemistry and
Cell Biology, Vol. 42, No. 12, 2010, pp. 2037-2046.
[64] J. Lin, R. M. Adam, E. Santiestevan and M. R. Freeman,
“The Phosphatidylinositol 30-Kinase Pathway Is a Do-
minant Growth Factor-Activated Cell Survival Pathway
in LNCaP Human Prostate Carcinoma Cells,” Cancer
Research, Vol. 59, No. 12, 1999, pp. 2891-2897.
[65] M. E. Cox, P. D. Deeble, S. Lakhani and S. J. Parsons,
“Adquisition of Neuroendocrine Characteristics by Pros-
tate Tumor Cells Is Reversible: Implicatios for Prostate
Cancer Progression,” Cancer Research, Vol. 59, No. 15,
1999, pp. 3821-3830.
[66] M. E. Hernandez, A. Soto-Cid, F. Rojas, L. I. Pascual, G.
E. Aranda-Abreu, R. Toledo, L. I. Garcia, A. Quintanar-
Stephano and J. Manzo, “Prostate Response to Prolactin
in Sexually Active Male Rats,” Reproductive Biology and
Endocrinology, Vol. 14, No. 4, 2006, pp. 28-38.
[67] K. E. Lane, I. Leav, J. Ziar, R. S. Bridges, W. M. Rand
and S. M. Ho, “Suppression of Testosterone and Estra-
diol-17beta-Induced Dysplasia in the Dorsolateral Pros-
tate of Noble Rats by Bromocriptine,” Carcinogenesis,
Vol. 18, No. 8, 1997, pp. 1505-1510.
[68] M. J. Linja, K. P. Porkka, Z. Kang, K. J. Savinainen, O. A.
Janne, T. L. J. Tammela, R. L. Vessella, J. J. Palvimo and
T. Visakorpi, “Expression of Androgen Receptor Co-
regulators in Prostate Cancer,” Clinical Cancer Research,
Vol. 10, No. 3, 2004, pp. 1032-1040.
[69] J. G. Ma, W. P. Li and Y. Q. Jiang, “Androgen Receptor
Mutation and Progression of Prostate Cancer,” Zhonghua
Nan Ke Xue, Vol. 17, No. 7, 2011, pp. 649-654.
[70] S. Sluczanowska-Glabowska, M. Laszczynska, M. Wylot,
W. Glabowski, M. Piasecka and D. Gacarzewicz, “Mor-
phological and Immunohistological Compare of Three
Rat Préstate Lobes (Lateral, Dorsal and Ventral) in Ex-
perimental Hyperprolactinemia,” Folia Histochemica et
Cytobiologica, Vol. 48, No. 3, 2010, pp. 447-454.
[71] S. K. Hong, J. H. Kim, M. F. Lin and P. R. K. JI, “The
Raf/MEK/Extracellular Signal-Regulated Kinase 1/2 Path-
way Can Mediate Growth Inhibitory and Differentiation
Signaling via Androgen Receptor Downregulation in
Prostate Cancer Cells,” Experimental Cell Research, Vol.
317, No. 18, 2011, pp. 2671-2682.
[72] S. H. Tan, A. Dagvadorj, F. Shen, L. Gu, Z. Liao, J. Ab-
dulghani, Y. Zhang, E. P. Gelmann, T. Zellweger, Z, Cu-
lig, T. Visakorpi, L. Bubendorf, R. A. Kirken, J. Karras
and M. T. Nevalainen, “Transcription Factor Stat5 Syner-
gizes with Androgen Receptor in Prostate Cancer Cells,”
Cancer Research, Vol. 68, No. 1, 2008, pp. 236-248.
[73] W. C. Guftason and W. A. Weiss, “Myc Proteins as Ther-
apeutic Targets,” Oncogene, Vol. 29, No. 9, 2010, pp.
1249-1259. doi:10.1038/onc.2009.512
[74] C. M. Koh, C. J. Bieberich, C. V. Dang, W. G. Nellson, S.
Yegnasubramanian and A. M. DeMarzo, “Myc and Pros-
tate Cancer,” Genes and Cancer, 2010, Vol. 1, No. 6, pp.
617-628. doi:10.1177/1947601910379132
[75] D. S. Rickman, T. D. Soonfg, B. Moss, J. M. Mosquera, J.
Dlabal, S. Terry, T. Y. MacDonald, J. Tripodi, K.
Bunting, V. Najfeld, F. Demichelis, A. M. Melnick, O.
Elemento and M. A. Rubin, “Oncogene-Mediated Altera-
tions in Chromatin Conformation,” Proceedings of the
National Academy of Sciences, 2012, Vol. 109, No. 23,
pp. 9083-9088. doi:10.1073/pnas.1112570109
[76] J. Wang, T. Kobayashi, N. Floch, C.W. Kinkade, A. Ay-
Copyright © 2012 SciRes. OJU
Copyright © 2012 SciRes. OJU
tes, D. Dankort, C. Lefevbre, A. Mitrofanova, R. D. Car-
diff, M. McMahon, A. Califano, M. M. Shen and C.
Anatte-Shen, “B-Raf Activation Cooperates with PTEN
Loss to Drive c-myc Expression in Advanced Prostate
Cancer,” Cancer Research, 2012, Vol. 72, No. 18, pp.
[77] M. D. Amatangelo, S. Goodyear, D. Varma and M. E.
Stearns, “c-Myc Expression and MEK1-Induced Erk2
Nuclear Localization Are Required for TGF-Beta Induced
Epithelial-Mesenchymal Transition and Invasion in Pros-
tate Cancer,” Carcinogenesis, 2012, Vol. 1, No. 1, pp.
1965-1975. doi:10.1093/carcin/bgs227
[78] S. Yamamura, S. Saini, S, Majid, H. Hirata, K. Ueno, G.
deng and R. Dahiya, “MicroRNA-34a Modulates c-myc
Transcriptional Complex to Suppress Malignancy in Hu-
man Prostate Cancer Cells,” Plos ONE, Vol. 7, No. 1, pp.
[79] B. Benassi, R. Flavin, L. Marchionni, S. Zanata, Y. Pan,
D. Chowdhury, M. Marani, S. Strano, P. Muti, G.
Blandino and M. Loda, “MYC Is Activated by USP2a-
Mediated Modulation of microRNAs in Prostate Cancer,”
Cancer Discovery, 2012, Vol. 2, No. 3, pp. 236-247.
[80] N. Nadiminty, R. Tummala, W. Lou, y. Zhu, J. Zhang, X.
Chen, W. R. eVere-White, H. J. Kung, C. P. Evans and A.
C. Gao, “MicroRNA let-7c Suppresses Androgen Re-
ceptor Expression and Activity via Regulation of Myc
Expression in Prostate Cancer Cells,” Jornal Biology
Chemistry, 2012, Vol. 287, No. 2, pp. 1527-1537.