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

Authors:
  • SRINAGESH ENDOCRINE CENTRE

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.
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
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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.
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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
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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]
... These hormones might directly influence the expression of genes, interact with signal transduction routes of steroid hormones, and probably mediate some properties of steroid actions [22]. The peptide hormone prolactin (PRL) is secreted mainly by the pituitary gland and, to a lesser extent, by peripheral tissues, such as the breast, decidua, prostate, and the brain, and it is involved in a broad spectrum of physiological processes in vertebrates [23]. The principal stimulatory and inhibitory control of prolactin secretion is a hypothalamic hormone that inhibits the prolactin secretion the dopamine. ...
... Clinical and experimental studies have demonstrated the pleiotropic role of prolactin, stimulating cellular proliferation and secretory activity in the prostate, under normal or pathological conditions [27]. PRL has been associated with a number of different forms of cancer, among them human breast and prostate cancer [23,25]. Besides, hyperprolactinemy is associated with amenorrhea, galactorrhea, pseudo-pregnancy and infertility in women [28]. ...
... Besides, hyperprolactinemy is associated with amenorrhea, galactorrhea, pseudo-pregnancy and infertility in women [28]. Human patients with benign prostatic hyperplasia or prostate cancer have higher blood levels of PRL [23]. Hyperprolactinemia caused enlargement and inflammation of the lateral rat prostate [29]. ...
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Background: The male and female prostates are controlled by steroid hormones, suffering important morphological and physiological changes after castration. Prolactin is involved in the regulation of the male prostate, having already been identified in the tissue, acting through its receptor PRLR. In the Mongolian gerbil, in addition to the male prostate, the female prostate is also well developed and active in its secretion processes. The aim of the present study was to evaluate the effects of exposure to exogenous prolactin in the prostate of both intact and castrated male and female gerbils in order to establish if prolactin administration can sustain prostate cell activity in conditions of sexual hormone deprivation. Methods: The morphological analyses were performed by biometric analysis, lesion histological analysis and morphometric-stereological aspects. In addition, immune-cytochemical tests were performed for prolactin and its receptor, as well as for the receptors of androgen and oestrogen and serum prolactin dosage. All data were submitted to ANOVA or Kruskal-Wallis tests for comparison between groups. P < 0.05 was considered to be statistically significant. Results: The results showed a strong influence of prolactin on the morphology of the prostate, with the development of important epithelial alterations, after only 3 days of administration, and an expressive epithelial cell discard process after 30 days of administration. Prolactin acts in synergy with testosterone in males and mainly with oestrogens in females, establishing different steroid hormonal receptor immunoreactivity according to sex. It was also demonstrated that prolactin can assist in the recovery from some atrophic effects caused in the gland after castration, without causing additional tissue damage. Conclusions: The prolactin and its receptor are involved in the maintenance of the homeostasis of male and female gerbils, and also cause distinct histological alterations after exogenous exposure for 3 and 30 days. The effects of prolactin are related to its joint action on androgens and oestrogens and it can also assist in the recovery from the atrophic effects of castration.
... Whether the secretions of the uterine glands directly stimulate trophoblast invasion remains elusive. Increased prolactin levels have also been linked to the higher invasiveness of specific tumor types [234,236]. This correlation seems to be particularly strong in breast cancer. ...
... This correlation seems to be particularly strong in breast cancer. The similarity between prolactin and growth hormones and its influence on the JAK/STAT signaling pathway strongly indicate its impact on tumor invasiveness [236]. Hence, it is assumed that both trophoblast and tumor invasion are also affected and regulated by the hormonal products produced by cells of their microenvironments [215,236]. ...
... The similarity between prolactin and growth hormones and its influence on the JAK/STAT signaling pathway strongly indicate its impact on tumor invasiveness [236]. Hence, it is assumed that both trophoblast and tumor invasion are also affected and regulated by the hormonal products produced by cells of their microenvironments [215,236]. ...
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... Prolactin has an important role in lactation but has since expanded to encompass an array of functions, ranging from metabolic homeostasis to maternal behaviour [47]. In gynaecological cancers, prolactin is implicated in ovarian and endometrial cancer, where PRLR is found to be upregulated [134]. Linher-Melville et al., found prolactin stimulated the expression and activity of CPTIA in MDA-MB-231 cells, in an AMPK-dependent manner. ...
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Gynaecological cancers are among the leading causes of cancer-related death among women worldwide. Cancer cells undergo metabolic reprogramming to sustain the production of energy and macromolecules required for cell growth, division and survival. Emerging evidence has provided significant insights into the integral role of fatty acids on tumourigenesis, but the metabolic role of high endogenous oestrogen levels and increased gynaecological cancer risks, notably in obesity, is less understood. This is becoming a renewed research interest, given the recently established association between obesity and incidence of many gynaecological cancers, including breast, ovarian, cervical and endometrial cancers. This review article, hence, comprehensively discusses how FA metabolism is altered in these gynaecological cancers, highlighting the emerging role of oestradiol on the actions of key regulatory enzymes of lipid metabolism, either directly through its classical ER pathways, or indirectly via the IGIFR pathway. Given the dramatic rise in obesity and parallel increase in the prevalence of gynaecological cancers among premenopausal women, further clarifications of the complex mechanisms underpinning gynaecological cancers are needed to inform future prevention efforts. Hence, in our review, we also highlight opportunities where metabolic dependencies can be exploited as viable therapeutic targets for these hormone-responsive cancers.
... In this case, dopaminergic agonists may play an important pharmacological role by lowering prolactin levels and reducing liver metastases [68]. Long-term hyperprolactinemia may be a risk factor for the onset of breast or prostate cancer [69], and for an unfavorable evolution of oncological disease [70]. The involvement of dopamine in cancer remains intensely debated, which on the one hand can promote the development of cancer and on the other hand can induce apoptosis of cancer cells, depending on the mechanisms involved in oncogenesis [71,72]. ...
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... Hyperprolactinemia was almost always detected in individuals with metastatic breast cancer during the course of the disease, and it was a significant indicator of poor prognosis in node-positive breast cancer patients (17). Prolactin may boost the survival of breast cancer cells by inducing the production of new cancer cells and inhibiting cell death via the Janus-activated kinase-2/signal transducers and activators of transcription-5 (JAK2/STAT5) signaling pathway (18). Prolactin-estrogen crosstalk is bidirectional and can happen at var ious levels. ...
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Background and objectives: Prolactin is a lactogenic protein hormone secreted by the anterior pituitary that initiates and maintains lactation in mammals. Previous research has linked increased serum prolactin levels to breast cancer. However, there is a paucity of studies in the Indian population on the subject. The present study evaluated and compared serum prolactin levels in patients with breast cancer and patients with benign breast diseases. Methods: This cross-sectional, comparative study was carried out at the Government Medical College, Nagpur (India) on patients with breast diseases in the out-patient department/in-patient department from June 2018 to November 2020. Breast cancer patients were considered cases, and those with benign breast diseases were considered controls. Breast carcinoma diagnosis was based on clinical features, fine needle aspiration cytology, and tissue histopathology in operated specimens for each patient. Fasting serum prolactin levels were measured by the chemiluminescence immunoassay method using the Advia Centaur immunoassay system. Results: There were 120 female patients with breast diseases, of whom 60 had breast malignancy, and 60 had benign breast diseases. The mean age of patients with benign breast disease and breast cancer was 33.17 (1.75) and 49.77 (1.16) years, respectively (P40.2 ng/ml) to differentiate breast cancer from benign breast diseases using the receiver operating characteristic curve analysis. Conclusion: Patients with breast cancer have increased serum prolactin levels compared to patients with benign breast diseases. Thus, serum prolactin level can be used as a diagnostic marker for breast cancer. This is particularly beneficial to clinicians for differentiating breast cancer from benign breast diseases.
... PRL promotes the initiation and progress of different gynecological neoplasms through different mechanisms. Furthermore, it is known that they share the cellular effects exerted through the JAK/STAT signaling cascade, such as survival, cell cycle progression, proliferation, migration, high metabolic rates, angiogenesis, and anti-apoptosis (9,12,(29)(30)(31)(32)(33)(34)(35)(36). In addition to this, it has been found that the PRLR is overexpressed in breast (14,37), cervical (38)(39)(40), ovarian (41,42), and endometrial cancer (EC) (2,43) in comparison with their respective cancer-free tissues. ...
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Prolactin (PRL) is a hormone produced by the pituitary gland and multiple non-pituitary sites, vital in several physiological processes such as lactation, pregnancy, cell growth, and differentiation. However, PRL is nowadays known to have a strong implication in oncogenic processes, making it essential to delve into the mechanisms governing these actions. PRL and its receptor (PRLR) activate a series of effects such as survival, cellular proliferation, migration, invasion, metastasis, and resistance to treatment, being highly relevant in developing certain types of cancer. Because women produce high levels of PRL, its influence in gynecological cancers is herein reviewed. It is interesting that, other than the 23 kDa PRL, whose mechanism of action is endocrine, other variants of PRL have been observed to be produced by tumoral tissue, acting in a paracrine/autocrine manner. Because many components, including PRL, surround the microenvironment, it is interesting to understand the hormone's modulation in cancer cells. This work aims to review the most important findings regarding the PRL/PRLR axis in cervical, ovarian, and endometrial cancers and its molecular mechanisms to support carcinogenesis.
... In the estrogen signaling pathway, estrogen exposure to chronic inflammatory disease activity is a key risk in breast cancer progression [76]. With regards to the prolactin signaling pathway, prolactin functions as a cytokine immune system, especially in breast cancer, which has the strongest correlation with an increased expression level of prolactin and prolactin receptors [77,78]. In the thyroid signaling pathway, the optimal regulation of the cellular thyroid hormone is essential for an adequate role of immune cells during inflammation [79]. ...
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