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Prolactin and cancer: Has the orphan finally found a home?

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Bipin Kumar Sethi
Bipin Kumar Sethi
Bipin Kumar Sethi
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G.V. Chanukya
G.V. Chanukya
G.V. Chanukya
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V. Nagesh at SRINAGESH ENDOCRINE CENTRE
V. Nagesh
  • SRINAGESH ENDOCRINE CENTRE
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Abstract

Prolactin has, for long, been associated with galactorrhea and infertility in women while its role in men is largely unknown. Recently, expression of prolactin in various other tissues like the breast, prostate, decidua, and the brain has been recognized. This has led to evaluation of paracrine and autocrine actions of prolactin at these tissues and a possible role in development of various cancers. Increased expression of PRL receptors has also been implicated in carcinogenesis. Breast cancer has the strongest association with increased prolactin and prolactin receptor levels. Prostate cancer also has reported significant association, while the role of prolactin in colorectal, gynecological, laryngeal, and hepatocellular cancers is more tenuous. Prolactin/prolactin receptor pathway has also been implicated in development of resistance to chemotherapy. Thus, the effects of this pathway in carcinogenesis seem widespread. At the same time, they also offer an exciting new approach to hormonal manipulation of cancers, especially the treatment-resistant cancers.
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Indian Journal of Endocrinology and Metabolism / Vol 16 / Supplement 2 S195
Prolactin and cancer: Has the orphan nally found
a home?
Bipin Kumar Sethi, G.V. Chanukya, V. Sri Nagesh
Department of Endocrinology and Metabolism, Care Hospitals, Banjara Hills, Road Number 1, Hyderabad - 500 034, Andhra, Pradesh, India
ABSTRACT
Prolactin has, for long, been associated with galactorrhea and infertility in women while its role in men is largely unknown. Recently,
expression of prolactin in various other tissues like the breast, prostate, decidua, and the brain has been recognized. This has led
to evaluation of paracrine and autocrine actions of prolactin at these tissues and a possible role in development of various cancers.
Increased expression of PRL receptors has also been implicated in carcinogenesis. Breast cancer has the strongest association with
increased prolactin and prolactin receptor levels. Prostate cancer also has reported signicant association, while the role of prolactin
in colorectal, gynecological, laryngeal, and hepatocellular cancers is more tenuous. Prolactin/prolactin receptor pathway has also been
implicated in development of resistance to chemotherapy. Thus, the effects of this pathway in carcinogenesis seem widespread. At the
same time, they also offer an exciting new approach to hormonal manipulation of cancers, especially the treatment-resistant cancers.
Key words: Prolactin, cancer, carcinogenesis
Mini Review
inTRoducTion
Prolactin (PRL), the peptide hormone secreted by the
anterior pituitary gland, has, for long, remained restricted
to the eld of lactation and infertility. While a few studies
recently have dealt with the use of prolactin in differentiating
true and pseudo- seizures, the multiple effects of this
hormone have largely remained unknown. The connection
between prolactin and cancer has been suspected for many
years, but never conclusively proven. The similarity of
prolactin with growth hormone and its actions through the
growth-promoting JAK/STAT pathway suggest its tumor-
promoting effects. Recent research has underlined the role
of PRL and PRL receptor (PRLR) most importantly in
breast and prostate cancers, but also in a variety of other
cancers. This review article has been designed to present
an overview of the recent understanding regarding role of
PRL in cancer and new modalities of cancer therapy based
on the PRL pathway.
Breast cancer
Breast cancer is one of the commonest cancers in women,
with over one million cases reported worldwide, making up
25% of all cancers in women. In spite of the availability
of advanced treatments like surgery, chemotherapy, and
radiotherapy, the disease continues to take its toll, with a
high incidence of treatment failure due to tumor resistance,
both intrinsic and acquired. This has prompted the search
for factors causing it and also the means to counteract
it, and prolactin is one such candidate. The concept of
prolactin as a factor in mammary cancer is not new. It was
initially suggested over three decades ago, based on data
obtained from murine models. For a long time, this animal
data could not be extrapolated to humans due to variety
of reasons: (i) most of these studies involved only a few
subjects, (ii) a concept of local production of prolactin in
breast tissue did not exist, (iii) most of the studies, which
used bromocriptine to reduce serum prolactin levels, did
not lead to successful treatment, and (iv) most of these
Corresponding Author: Bipin Kumar Sethi Department of Endocrinology and Metabolism, Care Hospitals, Banjara Hills, Road Number 1,
Hyderabad - 500 034, Andhra, Pradesh, India. E-mail: bipinkumarsethi@yahoo.co.uk
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DOI:
10.4103/2230-8210.104038
[Downloaded free from http://www.ijem.in on Friday, June 4, 2021, IP: 178.171.21.129]
Indian Journal of Endocrinology and Metabolism / Vol 16 / Supplement 2
S196
studies did not reach specic conclusions about the relation
between prolactin and breast cancer. However, the high
incidence of treatment failure and a number of recent
epidemiological studies have again shifted the focus back
on to prolactin. These recent studies have brought to fore,
a few critical concepts regarding the role of prolactin
(PRL) in breast cancer. (i) Even high-normal circulating
levels of PRL increase breast cancer risk. (ii) Locally
produced prolactin acts as an autocrine/paracrine factor in
breast cancer evolution. (iii) A causal relationship between
prolactin receptor expression and breast cancer has also
been recognized.[1]
The exact mechanism by which high-normal circulating
levels of PRL leads to increased breast cancer risk is not
exactly known. PRL may promote breast cancer via the
JAK2/STAT5 signaling pathway and may also increase the
survival of breast cancer cells by stimulating generation
of new cancer cells and decreasing cell death. PRL could
also increase cell motility and promote cancer spread. PRL
has also been implicated in causing resistance to cytotoxic
drugs like cisplatin and drugs like paclitaxel, which act on
cellular microtubules.
Circulating prolactin produced by the pituitary is not
the only prolactin available to tissues. Many organs
like the mammary gland, prostate, brain, deciduas, and
skin also express PRL. This extra-pituitary prolactin
probably is involved in development of breast tissue,
dermatological bio-regulation, and perception of pain.
While extra-pituitary secretion has also been reported in
animal models, it is assumed to be much more common
in humans and is dopamine and POU1F1-independent.
A specic regulator of local PRL production has still not
been identied, even though insulin, progesterone, and
transforming growth factor – β have been proposed as
regulators. In the breast, PRL is produced in both the
stromal and epithelial compartments. Further, while very
little prolactin is produced locally, it is very important for
tumor formation due to local availability.
A few studies have also found that breast tumors also
express higher levels of the PRL receptor (PRLR) when
compared to adjacent healthy tissue.[2,3] Even low levels
of prolactin receptor expression are adequate to mediate
actions of PRL in breast cancer cell lines. A family
of prolactin receptor (PRLr) isoforms, numbering six,
mediates the effects of PRL in human tissue. These six
isoforms are variably expressed in normal tissues and
malignant tissues. PRLR-triggered signaling cascades
have also been implicated in benign breast tumors. A
study by Plotnikov et al.[4] found that impaired turnover
of the prolactin receptor in breast cancer cells results in
accelerated proliferation and increased invasive growth.
Conversely, antagonism of the prolactin receptor
resulted in reduction of clonogenic capacity of breast
cancer cells and potentiated the action of cytotoxic anti-
cancer drugs.[5] This has very important implications in
chemotherapy of breast cancer, especially the resistant
types. The local production of prolactin cannot be
controlled by conventional dopamine agonists that act
at the pituitary level. This failure of bromocriptine
(the most commonly used dopamine agonist in cancer
studies) to reduce local PRL levels resulted in the failure
of this drug in cancer studies. This highlights the need
to develop a special category of therapeutic agents
targeted at reducing the action of endogenous PRL by
blocking the PRL receptor. The human PRLR antagonist
G129R-hPRL, which sterically hinders the sequential
dimerization and subsequent activation of the PRLR,
causes apoptosis of both estrogen receptor-positive and
estrogen receptor-negative breast cancer cell lines. In
the study by Howell et al.,[5] the ‘pure’ prolactin receptor
antagonist Δ1–9 signicantly augmented the cytotoxic
effects of doxorubicin and paclitaxel in vitro. This therapy
also inhibited the colony-forming efciency of cell lines
and primary cancers. Autocrine prolactin in breast cancer
cell lines can also be antagonized by prolactin-neutralizing
antibodies.[6] Most of the studies on antibodies have been
in vitro, in which these neutralizing antibodies have been
shown to inhibit MCF-7 and T47Dco cell growth and
to increase cell apoptosis.[7] Thus, these studies suggest
that a judicious combination of cytotoxic agents, PRLR
antagonists/neutralizing antibodies could provide a new
form of therapy for resistant breast cancers. At the
genetic level, construction of a PRLR single nucleotide
polymorphism risk prole for affected patients could
enable personalized treatment strategies.
Interactions between estrogen and prolactin systems
Recent research has indicated significant interaction
between estrogen and prolactin systems. Estrogen
stimulates prolactin secretion and can also up-regulate
human prolactin receptor gene expression and stimulate
growth of tumorigenesis.[8] Prolactin has been shown to
exert some of its effects on mammary tumor cells via the
estrogen receptor. Anti-estrogens like tamoxifen have also
been found to block the prolactin receptors. This could
represent another pathway of cancer therapy, discrete from
the anti-estrogenic effects of these drugs. Interestingly,
hyperprolactinemia results in hypogonadism, suppresses
the ovarian reproductive cycle, and reduces estrogen. Thus,
the interactions between prolactin and estrogen pathways
are complex, and careful studies are needed to formulate
treatment strategies.
Sethi, et al.: Prolactin cancer
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Indian Journal of Endocrinology and Metabolism / Vol 16 / Supplement 2 S197
pRosTaTe canceR
Prostate cancer is presently the most frequently diagnosed
cancer and represents the second most common cause
of death from cancer in men. PRL has an important
role in the development of prostate gland. In 1955,
Grayhack[9] discovered that when prolactin was inhibited
in rats during embryonic development, only 80% of
the prostate was developed, which shows that prolactin
is important in differentiation and development of
the prostate. There is also signicant evidence of the
existence of prolactin’s paracrine and autocrine actions.
The mainstay of treatment of prostate cancer includes
radical prostatectomy, radiation, and androgen deprivation
therapy. However, just like in breast cancer, resistance
to hormone therapy has also been noted in prostate
cancer. Also, prostate cancer often metastasizes to
the bone, which makes treatment even more difcult.
Epidemiological studies exploring a correlation between
serum PRL levels and prostate cancer incidence or severity
have been equivocal. Both malignant and healthy prostates
produce PRL. The PRL-positive tissues show a good
correlation with activated Stat5 and a high Gleason score.
Prostatic uids from patients with cancer also have higher
PRL levels than controls, which also lend support to the
existence of prostate-derived PRL. Most of the effects of
prolactin on prostate cancer cells are similar to those on
breast cancer cells. In vitro, prolactin induces proliferation
and antagonizes apoptosis in prostate organ culture and in
some tumor cell lines. In humans, receptors for prolactin
are expressed in the prostate, and this expression is
particularly elevated in prostate cancer and carcinoma in
situ. While hypogonadism caused by hyperprolactinemia
could have a role in reduction of prostate cancer, as
reported in a study,[10] the bulk of evidence seems to
suggest that up-regulation of PRLR and local production
of PRL in prostate could be important in increased risk
of prostate cancer and treatment resistance.
coloRecTal canceR
Colorectal cancer is the third highest cause of cancer
mortality worldwide. CEA is the most common marker
utilized for the detection and follow-up of colorectal
cancer. However, a study by Soroush et al.[11] compared
serum PRL and CEA level of 47 patients and found that
serum PRL and CEA levels were increased in patients
with colorectal cancer, but the greater portion of the
patients had an increased level of PRL compared with
elevated level of CEA. They also found no correlation
between the plasma PRL concentration and the stage of
the tumor. They concluded that in view of the high cost
of CEA, prolactin could be used as a tumor marker for
colorectal cancer. Similar results have been found in a study
by Bhatavdekar.[12] However, evidence about the role of
prolactin in colorectal cancer has been mixed, and its role
in colorectal cancer remains contentious.
hepaTocellulaR caRcinoma
Hepatocellular carcinoma (HCC) accounts for more than
6 lakh new cases per year worldwide. Despite several
treatment modalities, the long-term survival rate remains
unsatisfactory, principally due to high rates of recurrence
and metastasis even after treatment. Increased circulating
prolactin levels, high p-JAK2 expression, and generation
of liver cancer cells through PRLR/JAK2 signaling have all
been proposed as mechanisms that could contribute to the
development of HCC. A study by Yeh et al.[13] demonstrated
signicantly higher serum levels of prolactin in people with
HCC, and this signicant relationship existed irrespective
of gender, age, or BMI. These ndings have signicant
implications in the detection and therapy of HCC, if
proven. Hence, larger studies, which can prove the role
of PRL in activation of JAK2 and exclude the role of
other cytokines and growth factors in the JAK2 activation
pathway, need to be designed immediately.
gynecological canceRs
Elevated levels of serum PRL in ovarian and endometrial
cancers have been reported, indicating a potential role for
PRL in gynecological cancers. PRL possibly promotes
tumorigenesis by activating Ras oncogene, and thus
could lead to cells with mutations in tumor suppressor
genes turning malignant. A study by Levina et al.[14] found
dramatically increased expression of PRL receptor in
ovarian and endometrial tumors as well as in endometrial
hyperplasia, signifying the importance of PRL signaling in
malignant and premalignant conditions. PRL mRNA was
expressed in ovarian and endometrial tumors, indicating
the presence of an autocrine loop. Serum PRL levels were
also signicantly elevated in women with a strong family
history of ovarian cancer, and this PRL rise could not be
attributed to stress.
malignanT laRyngeal TumoRs
Laryngeal cancer (LC) is responsible for approximately
159,000 new cases and 90,000 mortalities every year. The
mechanisms underlying the proliferation of this form of
cancer are not yet fully understood. A recent study by
González-Lucano et al.[15] found increased expression of
different isoforms of PRLR in LC in comparison with
recurrent respiratory papillomatosis. This suggested a
Sethi, et al.: Prolactin cancer
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Indian Journal of Endocrinology and Metabolism / Vol 16 / Supplement 2
S198
possible role of PRL/PRLR in the development of LC.
They concluded that PRLR might be useful as a target for
further investigations in laryngeal tissues.
all cause moRTaliTy
In view of the widespread expression of PRL in various
tissues and the emerging role of prolactin in causing
multiple cancers, a study was devised by Berinder et al.[10]
to assess the overall relative risk of cancer and risk of
some specic a priori specied cancer forms in a cohort
of 969 women and men with hyperprolactinemia. Their
results were different from the majority of prolactin and
cancer studies, and they reported a higher incidence of
upper gastrointestinal cancer in both males and females
and hematopoietic cancer in females. Risk of breast cancer
was not increased in women, and there was a reduced risk
of prostate cancer in men. An increased overall cancer risk
was found in hyperprolactinemia patients.
The last word on the role of PRL in causing cancer and
on its receptor conferring resistance to chemotherapeutic
agents is yet to be written. The more the number of cancers
added to the list, the more is the story getting curiouser and
curiouser. Clearly, an association has been demonstrated,
but whether that is a cause and effect relationship is yet
to be established. The modest PRL elevations could
be of local origin. Higher levels that are obtained in
prolactinomas usually cause hypogonadism, something that
chemotherapies for breast and prostate cancer treatment
aim at, and hence this high serum PRL certainly cannot be
blamed for causing these cancers.
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Cite this article as: Sethi BK, Chanukya GV, Nagesh VS. Prolactin and cancer:
Has the orphan nally found a home?. Indian J Endocr Metab 2012;16:S195-8.
Source of Support: Nil, Conict of Interest: None declared.
Sethi, et al.: Prolactin cancer
[Downloaded free from http://www.ijem.in on Friday, June 4, 2021, IP: 178.171.21.129]
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Article
  • Jun 2023
Objective: the main aim of this study was to assess the role of prolactin in prostate cancer using modern immunoassay methods. Prolactin assays in the past were subject to pitfalls from hook effect and macroprolactinemia; only few previous studies accounted for these pitfalls, therefore and to obtain accurate results, we thought to measure prolactin with modified modern methods. This study also investigated the association of serum prolactin levels with prostate specific antigen and selected steroid and pituitary hormones in prostate cancer patients. Subjects and Methods: serum was withdrawn from newly pretreated 50 prostate cancer patients and 30 controls. The following parameters were studied using Roche-immunoassay analyzers: prolactin, total (PSA), total testosterone, free testosterone, (SHBG), (DHEA), (E2), progesterone, (FSH), (LH) and albumin; to account for macroprolactinemia, serum samples were pretreated with poly ethylene glycol 6000. SPSS statistical software used to perform students’ t test and Pearson’s correlation for association studies. P value of < 0.05 was considered significant throughout the study. Results: 64% of prostate cancer patients had normal prolactin levels (10.04 ±0.039ng/ml), 22% had raised serum prolactin and had 14% low prolactin levels, the difference in prolactin levels between prostate cancer and control group was not significant. Mean PSA levels were ((234.087 ± 522.695ng/ml) in prostate cancer patients, which was significantly higher in the prostate cancer group when compared to the control group (1.25 ± 1.39ng/ml), P ≤ 0.01. Prolactin was not associated with PSA levels or with any of the sex and pituitary hormones studied. Conclusions: although the majority of prostate cancer patients had normal serum prolactin levels, 22% of the study participants had hyperprolactinemia, patients with higher serum prolactin levels had high Gleason score of 9 or higher and were at stage four, indicating a possible role of higher circulating prolactin at advanced cancer stages.
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A role for JAK2 in mediating cell surface GHR-PRLR interaction
Preprint
Full-text available
  • Oct 2023
Growth hormone (GH) receptor (GHR) and prolactin (PRL) receptor (PRLR) are transmembrane class I cytokine receptors that co-exist in various normal and cancerous cells. Both receptors respond to their associated ligands predominantly by activating the Janus Kinase 2 (JAK2)-signal transducer and activator of transcription (STAT) signaling pathways, and both are also known to initiate receptor-specific JAK2-independent signaling. Together with their cognate ligands, these receptors have been associated with pro-tumorigenic effects in various cancers, including breast cancer (BC). Human GH is known to bind GHR and PRLR, while PRL can only bind PRLR. A growing body of work suggests that GHR and PRLR can form heteromers in BC cells, modulating GH signal transduction. However, the dynamics of PRLR and GHR on the plasma membrane and how these could affect their respective signaling still need to be understood. To this end, we set out to unravel the spatiotemporal dynamics of GHR and PRLR on the surface of human T47D breast cancer cells and γ2A-JAK2 cells. We applied direct stochastic optical reconstruction microscopy (dSTORM) and quantified the colocalization and availability of both receptors on the plasma membrane at the nanometer scale at different time points following treatment with GH and PRL. In cells co-expressing GHR and PRLR, we surprisingly observed that not only GH but also PRL treatment induces a significant loss of surface GHR. In cells lacking PRLR or expressing a mutant PRLR deficient in JAK2 binding, we observed that GH induces downregulation of membrane-bound GHR, but PRL no longer induces loss of surface GHR. Colocalizations of GHR and PRLR were confirmed by proximity ligation (PL) assay. Our results suggest that PRLR-GHR interaction, direct or indirect, is indispensable for PRL-but not GH-induced loss of surface GHR and for both GH-induced and PRL-induced increase of surface PRLR, with potential consequences for downstream signaling. Furthermore, our results suggest that JAK2 binding via the receptor intracellular domain’s Box1 element is crucial for the observed regulation of one class I cytokine receptor’s cell surface availability via ligand-induced activation of another class I cytokine receptor. Our findings shed new light on the reciprocal and collective role that PRLR and GHR play in regulating cell signaling.
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A role for JAK2 in mediating cell surface GHR-PRLR interaction
Preprint
Full-text available
  • Sep 2023
Growth hormone (GH) receptor (GHR) and prolactin (PRL) receptor (PRLR) are transmembrane class I cytokine receptors that co-exist in various normal and cancerous cells. Both receptors respond to their associated ligands predominantly by activating the Janus Kinase 2 (JAK2)-signal transducer and activator of transcription (STAT) signaling pathways, and both are also known to initiate receptor-specific JAK2-independent signaling. Together with their cognate ligands, these receptors have been associated with pro-tumorigenic effects in various cancers, including breast cancer (BC). Human GH is known to bind GHR and PRLR, while PRL can only bind PRLR. A growing body of work suggests that GHR and PRLR can form heteromers in BC cells, modulating GH signal transduction. However, the dynamics of PRLR and GHR on the plasma membrane and how these could affect their respective signaling still need to be understood. To this end, we set out to unravel the spatiotemporal dynamics of GHR and PRLR on the surface of human T47D breast cancer cells and γ2A-JAK2 cells. We applied direct stochastic optical reconstruction microscopy (dSTORM) and quantified the colocalization and availability of both receptors on the plasma membrane at the nanometer scale at different time points following treatment with GH and PRL. In cells co-expressing GHR and PRLR, we surprisingly observed that not only GH but also PRL treatment induces a significant loss of surface GHR. In cells lacking PRLR or expressing a mutant PRLR deficient in JAK2 binding, we observed that GH induces downregulation of membrane-bound GHR, but PRL no longer induces loss of surface GHR. Colocalizations of GHR and PRLR were confirmed by proximity ligation (PL) assay. Our results suggest that PRLR-GHR interaction, direct or indirect, is indispensable for PRL-but not GH-induced loss of surface GHR and for both GH-induced and PRL-induced increase of surface PRLR, with potential consequences for downstream signaling. Furthermore, our results suggest that JAK2 binding via the receptor intracellular domain’s Box1 element is crucial for the observed regulation of one class I cytokine receptor’s cell surface availability via ligand-induced activation of another class I cytokine receptor. Our findings shed new light on the reciprocal and collective role that PRLR and GHR play in regulating cell signaling.
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Haloperidol Instigates Endometrial Carcinogenesis and Cancer Progression by the NF-κB/CSF-1 Signaling Cascade
Article
Full-text available
  • Jun 2022
Haloperidol is a routine drug for schizophrenia and palliative care of cancer; it also has antitumor effects in several types of cancer. However, the role of haloperidol in endometrial cancer (EC) development is still unclear. Here, we show that chronic haloperidol treatment in clinically relevant doses induced endometrial hyperplasia in normal mice and promoted tumor growth and malignancy in mice with orthotopic EC. The pharmacokinetic study indicated that haloperidol highly accumulated in the uterus of mice. In vitro studies revealed that haloperidol stimulated the cellular transformation of human endometrial epithelial cells (HECCs) and promoted the proliferation, migration, and invasion of human endometrial carcinoma cells (HECCs) by activating nuclear factor kappa B (NF-κB) and its downstream signaling target, colony-stimulating factor 1 (CSF-1). Gain of function of CSF-1 promotes the cellular transformation of HEECs and the malignant progression of HECCs. Moreover, blockade of CSF-1 inhibited haloperidol-promoted EC progression in vitro and in vivo. A population-based cohort study of EC patients further demonstrated that the use of haloperidol was associated with increased EC-specific mortality. Collectively, these findings indicate that clinical use of haloperidol could potentially be harmful to female patients with EC.
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Prolactin Promotes Hepatocellular Carcinoma through Janus Kinase 2
Article
Full-text available
  • Mar 2012
  • WORLD J SURG
Hepatocellular carcinoma (HCC) is one human cancer with obvious gender disparity. This study investigated the association of aberrant prolactin levels with HCC risk and the potential impacts on HCC of the prolactin receptor (PRLR)/Janus kinase 2 (JAK2) signaling. Serum prolactin of 63 HCC patients and 162 subjects without HCC was measured by radioimmunoassay. The expressions of PRLR and phosphorylated JAK2 (p-JAK2) in 82 retrospectively collected HCC specimens were evaluated by immunohistochemistry and further incorporated into the survival analysis. The immunoblotting and proliferation assays were used to analyze the effects of PRLR/JAK2 signaling on liver cancer cells with prolactin treatment. Serum prolactin level was significantly higher in HCC patients than in controls. Hepatocellular carcinoma patients with high p-JAK2 expression had a significantly higher postoperative risk than those with low p-JAK2 expression. Moreover, results from the multivariate analysis indicated the prognostic role of p-JAK2 expression with respect to overall survival in HCC patients. In addition, the Kaplan-Meier survival curve showed that high p-JAK2 expression was associated with poor survival in HCC patients with high PRLR expression. The immunoblotting assay showed that prolactin induced the expression of both p-JAK2 and cyclin D1 in Hep-G2 cells. Importantly, the proliferative effects induced by prolactin could be effectively attenuated by adding AG490, a JAK2 inhibitor. Increased circulating prolactin was found in HCC patients and high p-JAK2 expression could predict poor overall survival in those patients expressing high PRLR. In addition, prolactin contributed to the proliferation of liver cancer cells through PRLR/JAK2 signaling.
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New concepts in prolactin biology
Article
Full-text available
  • Apr 2010
  • J ENDOCRINOL
Human prolactin (PRL) is currently viewed as a hormone of pituitary origin, whose production (i.e. serum levels) is controlled by dopamine, whose biological actions relate exclusively to lactation and reproductive functions, for which any genetic disorder is yet to be identified, and whose unique associated pathology is hyperprolactinemia. Both experimental studies and human sample/cohort-based investigations performed during the past decade have considerably widened our perception of PRL biology: i) there are now strong epidemiological arguments supporting the fact that circulating PRL is a risk factor for breast cancer, ii) in addition to the endocrine hormone, locally produced PRL has been documented in several human tissues; there is increasing evidence supporting the tumor growth potency of local PRL, acting via autocrine/paracrine mechanisms, in both rodent models, and human breast and prostate tumors, iii) the first functional germinal polymorphisms of the PRL receptor were recently identified in patients presenting with breast tumors, which involve single amino acid substitution variants exhibiting constitutive activity, iv) human PRL analogs have been engineered, which were shown in experimental models to down-regulate the effects triggered by local PRL (competitive antagonism) or by the constitutively active receptor variants (inverse agonism). The aim of this review is to discuss these novel concepts in PRL biology, including their potential pathophysiological outcomes.
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Biological Significance of Prolactin in Gynecologic Cancers
Article
Full-text available
  • Jul 2009
  • CANCER RES
There is increasing evidence that prolactin (PRL), a hormone/cytokine, plays a role in breast, prostate, and colorectal cancers via local production or accumulation. Elevated levels of serum PRL in ovarian and endometrial cancers have been reported, indicating a potential role for PRL in endometrial and ovarian carcinogenesis. In this study, we show that serum PRL levels are significantly elevated in women with a strong family history of ovarian cancer. We show dramatically increased expression of PRL receptor in ovarian and endometrial tumors as well as in endometrial hyperplasia, signifying the importance of PRL signaling in malignant and premalignant conditions. PRL mRNA was expressed in ovarian and endometrial tumors, indicating the presence of an autocrine loop. PRL potently induced proliferation in several ovarian and endometrial cancer cell lines. Binding of PRL to its receptor was followed by rapid phosphorylation of extracellular signal-regulated kinase (ERK) 1/2, mitogen-activated protein kinase/ERK kinase 1, signal transducer and activator of transcription 3, CREB, ATF-2, and p53 and activation of 37 transcription factors in ovarian and endometrial carcinoma cells. PRL also activated Ras oncogene in these cells. When human immortalized normal ovarian epithelial cells were chronically exposed to PRL, a malignant transformation occurred manifested by the acquired ability of transformed cells to form clones, grow in soft agar, and form tumors in severe combined immunodeficient-beige mice. Transformation efficiency was diminished by a Ras inhibitor, providing proof that PRL-induced transformation uses the Ras pathway. In summary, we present findings that indicate an important role for PRL in ovarian and endometrial tumorigenesis. PRL may represent a risk factor for ovarian and endometrial cancers.
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Impaired Turnover of Prolactin Receptor Contributes to Transformation of Human Breast Cells
Article
Full-text available
  • May 2009
  • CANCER RES
Signaling by polypeptide hormone prolactin (PRL) is mediated by its cognate receptor (PRLr). PRLr is commonly stabilized in human breast cancer due to decreased phosphorylation of residue Ser349, which when phosphorylated recruits the betaTrcp E3 ubiquitin ligase and facilitates PRLr degradation. Here, we show that an impaired PRLr turnover results in an augmented PRL signaling and PRL-induced transcription. Human mammary epithelial cells harboring degradation-resistant PRLr display accelerated proliferation and increased invasive growth. Conversely, a decrease in PRLr levels achieved by either pharmacologic or genetic means in human breast cancer cells dramatically reduced transformation and tumorigenic properties of these cells. Consequences of alteration of PRLr turnover for homeostasis of mammary cells and development of breast cancers, as well as the utility of therapies that target PRLr function in these malignancies, are discussed.
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Increased induction of the prolactin receptor is associated with malignant laryngeal tumors
Article
  • Apr 2012
  • Exp Ther Med
The altered expression of the prolactin receptor (PRLR) has been associated with the development of various types of cancer, particularly breast, prostate and endometrial cancer. However, in laryngeal tumors, the expression of PRLR has not yet been documented. The aim of this study was to determine the expression and localization of PRLR in laryngeal cancer (LC) in comparison with recurrent respiratory papillomatosis (RRP). PRLR expression was analyzed in 48 paraffin-embedded tissues (18 RRP and 30 laryngeal cancer tissues) by immunoperoxidase staining. Furthermore, PRLR expression was evaluated in ten samples from each group by Western blot analysis and quantitative real-time PCR. PRLR was observed in all laryngeal tumors at different intensities. PRLR overexpression was significantly associated (P<0.005) with LC. The staining pattern was homogeneous, mainly cytoplasmic, and confined to the tumor area. We found increased expression of different isoforms in LC in comparison with RRP. Our results suggest a possible role of PRL/PRLR in the development of LC. PRLR may be useful as a target for further investigations in laryngeal tissues.
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Cancer risk in hyperprolactinemia patients: A population-based cohort study
Article
  • May 2011
  • EUR J ENDOCRINOL
Experimental evidence indicates that prolactin might play a role in tumorigenesis of several human cancers, but data on cancer risk in hyperprolactinemia patients are sparse. The aim of this study was to investigate cancer risk in hyperprolactinemia patients. Design A population-based matched cohort study in Sweden. The hyperprolactinemia cohort consisted of patients hospitalized for hyperprolactinemia from 1987 to 1995 identified in the National Patient Register (n=585) and a hospital cohort of prolactinoma patients at Karolinska University Hospital (n=384). For each patient, ten matched individuals were identified via the Register of Population. Cancer occurrence was ascertained via the Swedish Cancer Registry. Hazard ratios (HRs) were estimated by Cox proportional hazards regression. Seventy-three malignant tumors were identified in the hyperprolactinemia patients and 660 tumors in the comparison group (HR 1.31; 95% confidence interval (CI): 1.02-1.68), mainly attributed to an increased risk of upper gastrointestinal cancer in both males and females (HR 3.69; 95% CI: 1.70-8.03) and hematopoietic cancer in females (HR 3.51; 95% CI: 1.06-11.6). Twelve breast cancers occurred in the female patients, corresponding to an HR of 1.09 (95% CI: 0.60-1.99). Prostate cancer risk in hyperprolactinemia men was reduced (HR 0.40; 95% CI: 0.16-0.99). An increased overall cancer risk was found in hyperprolactinemia patients, but no increased risk of breast cancer in women and a reduced risk of prostate cancer in men. These findings warrant further investigations and to be confirmed in larger studies but may indicate the importance of an active treatment strategy and follow-up of hyperprolactinemia patients.
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Amplification of the Prolactin Receptor Gene in Mammary Lobular Neoplasia.
Article
  • Jul 2011
  • BREAST CANCER RES TR
The identification of lobular carcinoma in situ (LCIS) in a patient's specimen confers an appreciable increased risk of development of future invasive mammary carcinoma. However, the study of LCIS presents a challenge as it is usually only recognized in fixed specimens. Recent advances in high throughput genomics have made possible comprehensive copy number analysis of lesions such as this. Using array comparative genomic hybridization (aCGH), we characterized eight cases of lobular carcinoma (four invasive and four non-invasive) from microdissected samples of archival specimens and validated our results by quantitative real-time PCR (qRT-PCR). Immunohistochemistry (IHC) was performed on an independent set of 80 in situ ductal (DCIS) and lobular breast lesions to confirm our results. Amplification of the prolactin receptor gene (PRLr) was identified in 4/4 cases of LCIS by aCGH. We confirmed this amplification by qRT-PCR and demonstrated PRLr expression in 29/40 (73%) cases of lobular neoplasia by IHC. Amplification of PRLr was neither detected in 10 cases of DCIS nor in 5 areas of normal breast tissue by qRT-PCR and only 14/40 (35%) cases of DCIS showed PRLr expression by IHC (P = 0.0008). Our study suggests the prolactin receptor gene is a molecular target that may be important in the pathogenesis and progression of lobular neoplasia. Investigation of the status of this gene in cases of DCIS has indicated that it may not be as important in the progression of this type of breast cancer, supporting the view that lobular and ductal carcinomas may evolve along separate pathways.
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Adiponectin, Resistin and Leptin Response to Dietary Intervention in Diabetic Nephropathy
Article
  • Jul 2010
  • J RENAL NUTR
Adipokines play an important role in metabolic regulations. Obesity, diabetes, and renal disturbances affect adipokine profile by influencing their complex effects on metabolism. Our objective was to assess the effect of low-energy diet intervention on serum adiponectin, leptin, and resistin levels in diabetic nephropathy. Seventeen subjects with diabetes type 2 and nephropathy participated in the study. After estimation of individual resting metabolic rates by indirect calorimetry, diets introducing 20% energy deficit were applied. At baseline and after 2 months of dieting, the following parameters were measured: body composition by dual x-ray spectrometry and serum adiponectin (Adp), leptin (Lep), resistin (Res), insulin, urea, creatinine, glucose, glycosylated hemoglobin, C-reactive protein, and tumor necrosis factor-alpha concentrations. Homeostatic model assessment (HOMA) was used to quantify insulin resistance. Total energy, protein, and fat intakes diminished significantly with intentional dieting. Significant decreases in total body fat mass (FM) and its percentage in body mass (FM%) and trunk and gynoid fat mass, as well as in serum resistin and tumor necrosis factor-alpha levels, were also observed. Responses of adipokines to dietary treatment varied individually. Generally, they were affected by FM. Alterations in Lep concentrations correlated negatively with baseline FM, FM%, and android and gynoid fat mass and positively with changes in intake of protein, carbohydrates, and total energy of the consumed diet. Changes in Adp were inversely related to FM after therapy. Alterations in Res concentrations correlated positively with android fat mass before therapy and initial Lep levels. Adiponectin was inversely related to HOMA index before and after treatment. Low-energy diet applied in diabetic nephropathy may decrease serum resistin levels and inflammation. In addition, responses of all adipokines to dieting appear to be affected by body fat mass, especially android fat mass.
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Growth-plate cartilage in chronic renal failure
Article
  • Oct 2009
  • PEDIATR NEPHROL
Bone growth occurs in the growth-plate cartilage located at the ends of long bones. Changes in the architecture, abnormalities in matrix organization, reduction in protein staining and RNA expression of factors involved in cell signaling have been described in the growth-plate cartilage of nephrectomized animals. These changes can lead to a smaller growth plate associated with decrease in chondrocyte proliferation, delayed hypertrophy, and prolonged initiation of mineralization and vascular invasion. As a result, chronic renal failure can result in stunted body growth and skeletal deformities. Multiple etiologic factors can contribute to impaired bone growth in renal failure, including suboptimal nutrition, metabolic acidosis, and secondary hyperparathyroidism. Recent findings have also shown the tight connection between chondro/osteogenesis, hematopoiesis, and immunogenesis.
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Human uraemic plasma stimulates release of leptin and uptake of tumour necrosis factor- in visceral adipocytes
Article
  • Sep 2009
  • NEPHROL DIAL TRANSPL
End-stage renal disease (ESRD) is commonly associated with anorexia, malnutrition and inflammation. In addition to serving as the primary reservoir for energy storage, adipocytes produce numerous pro- and anti-inflammatory mediators and regulate food intake by releasing the appetite-suppressing (leptin) and appetite-stimulating (adiponectin) hormones. Under normal conditions, release of leptin is stimulated by feeding to prevent excess intake, and release of adiponectin is stimulated by fasting to induce feeding. However, under certain pathological conditions such as inflammation, maladaptive release of these hormones leads to anorexia, wasting and malnutrition and simultaneously intensifies inflammation. Anorexia, malnutrition and inflammation in ESRD are frequently accompanied by hyper-leptinaemia. This study was designed to test the hypothesis that uraemic plasma may stimulate leptin release and suppress adiponectin release in normal adipocytes. Visceral adipose tissue was harvested from normal rats, and adipocytes were isolated and incubated for 2-4 h in media containing 90% plasma from 12 ESRD patients (before and after haemodialysis) and 12 normal control subjects. The ESRD group had a marked elevation of plasma TNF-alpha, IL-6, IL-8 and leptin concentrations before and after haemodialysis. Incubation in media containing plasma from the ESRD group elicited a much greater leptin release by adipocytes than that containing normal plasma. Post-dialysis plasma evoked an equally intense leptin release. The rise in leptin release was coupled with a parallel fall in TNF-alpha concentration in the incubation media. In contrast to leptin, adiponectin release in the presence of uraemic plasma was similar to that found with the control plasma. Exposure to uraemic plasma induces exuberant release of leptin that is coupled with avid uptake of TNF-alpha by visceral adipocytes. These observations confirm the role of TNF-alpha, formerly known as cachexin, in the over-production and release of leptin in patients with ESRD.
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