Prolactin: The Forgotten Hormone of Human Breast Cancer

doi:10.1016/S0163-7258(98)00017-5

Pharmacology & Therapeutics

Volume 79, Issue 2, August 1998, Pages 169-178

https://doi.org/10.1016/S0163-7258(98)00017-5 Get rights and content

Abstract

Prolactin (PRL) is both a mitogen and a differentiating agent in the mammary gland. It has been shown to be involved in mammary cancer development in rodents, but in human breast cancer, its role has long been overlooked. Three criteria are applied to demonstrate PRL’s involvement in this disease: (1) PRL receptors are present in human breast cancer cells, (2) human breast cancer cells in culture respond to PRL as a mitogen, and (3) PRL is synthesized by human breast cancer cells and inhibition of the binding of PRL to its receptors inhibits cell growth.

Introduction

One of the most intriguing questions in mammary gland biology is why prolactin (PRL), which clearly is involved in normal breast development in rodents and humans and clearly plays a role in rodent mammary cancer Welsch and Nagasawa 1977, Vonderhaar and Biswas 1987, has not been accepted as a player in human breast cancer. For any hormone, such as estrogen, to be accepted as playing a role in breast cancer, three criteria are applied. First, there must be specific receptors for the hormone on the cancer cells. Second, the hormone must induce a biological response. Third, the course of the disease must be altered when the action of the hormone is specifically inhibited at the target (as is the case with antiestrogens and estrogen effects) or the source of the hormone is removed, i.e., through ovariectomy. When these same criteria are applied to PRL, a role for this hormone in breast cancer can be argued.

Section snippets

Receptor Forms

The presence of specific receptors for PRL has been demonstrated in both normal and malignant mammary glands. PRL receptors belong to the cytokine hematopoietic family of receptors (Kelly et al., 1991). The members of this superfamily are single membrane-spanning receptors organized into three domains comprising an extracellular ligand-binding domain, a hydrophobic transmembrane domain, and an intracellular domain containing a proline-rich motif. The three different forms of the PRL receptor

Prolactin as Mitogen in Vivo

In the mammary gland, PRL is both a differentiating agent and a mitogen. It is the mitogenic action that is important in breast cancer. In the normal gland, PRL’s most fundamental actions are at the level of growth and maintenance of the morphology of the mammary gland. Although the ovarian steroids, estrogen and progesterone, are involved in the ductal growth and branching, lobulo-alveolar development and extensive growth of the alveolar cells in the rodent require PRL Vonderhaar 1984,

Serum Prolactin Levels in Breast Cancer Patients

Historically, the third criterion has been the most difficult to satisfy in terms of PRL’s action in human breast cancer. From 60 to 85% of human breast cancer biopsies contain immunologically detectable PRL Purnell et al. 1982, Agarwal et al. 1989, whereas specific PRL receptors have been demonstrated in over 70% of the biopsy samples Codegone et al. 1981, Peyrat et al. 1981, Bonneterre et al. 1982, L’Hermite-Baleriaux et al. 1984. However, there is no clear correlation between circulating PRL

Conclusion

The demonstration of synthesis of PRL by human breast cancer cells suggests that manipulation of pituitary PRL is not a valid approach to therapy for this disease and that new approaches based on the concept of an autocrine/paracrine PRL may be necessary. These observations suggest that the use of specific drugs acting as antilactogens (Das et al., 1994) or analogues of the hormone that antagonizes PRL action at the target tissue Dattani et al. 1995, Fuh and Wells 1995, Goffin et al. 1996, Mode

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Cited by (72)

Mucuna pruriens (L.) DC chemo sensitize human breast cancer cells via downregulation of prolactin-mediated JAK2/STAT5A signaling
2018, Journal of Ethnopharmacology
Citation Excerpt :
PRL mediates its actions by PRL receptor (PRLR) isoforms present on, or secreted by, human mammary cancer cells. PRL binds to PRLR forming a complex which further activates JAK2/STAT5A/B signaling cascades leading to the transcriptional activation of Cyclin D1, a well-known tumor promoting marker for human cancers including breast cancer (Radhakrishnan et al., 2012; Vonderhaar, 1998; Brockman et al., 2002). This suggest that blocking PRL synthesis not only at pituitary level but at extra pituitary level further targeting PRL/PRLR signaling pathway may be a beneficial therapeutic target against breast cancer.
Mucuna pruriens (L.) DC (MP) is an ancient Indian medicinal plant traditionally used to treat Parkinson's disease. L-Dopa (LD), precursor of dopamine is abundantly found in the seeds of MP. L-dopa is a natural inhibitor of prolactin (PRL) hormone which is required to maintain lactation in women but it's over production (hyperprolactinemia) plays critical role in advancement of breast cancer.
We aim to examine the pharmacological effect of LD and MP on this hyperprolactinemia associated breast cancer and related signaling for effective management of the disease. We also investigated chemo-sensitizing effect of MP on hyperprolactinemia-mediated cisplatin resistance.
Methanolic seed extract of MP were prepared and analysed using HPLC. Effect of LD and MP on the cellular viability of breast cancer cells (T47D, MCF-7, MDA-MB-468 and MDA-MB-231) were evaluated using MTT assay. Further, effect of LD and MP on colony forming potential, DNA damage, cell cycle distribution and apoptosis was determined using agar/agarose method, comet assay and annexin and PI method followed by FACS analysis. To reveal the molecular mechanism involved in the anti-cancer activity of MP, transcriptional and translational level analysis of the key proteins involved in the PRL-mediated signaling, was performed using RT-PCR and western blot analysis. The effect of MP extract on PRL-mediated signaling was validated using dopaminergic agonist bromocriptine. MP extract and cisplatin was given in different combination with appropriate controls to check their effect on chemo-resistivity of breast cancer cells.
Our results demonstrated that MP seed extract has the potential to inhibit cellular proliferation of PRL expressing T47D and MCF-7 breast cancer cells via induction of DNA damage, G1 phase of cell cycle arrest and apoptosis more effectively as compare to LD. Further, MP-mediated anti-cancerous effect was associated with the downregulation of PRL expression, further suppressing the JAK2/STAT5A/Cyclin D1 signaling pathway which has been validated using dopaminergic agonist bromocriptine. Cancer-related hyperprolactinemia confers cisplatin resistance, we observed that MP via PRL inhibition, enhances cisplatin efficacy after their combinatorial treatment in breast cancer cells.
Collectively, our study suggests that MP could be recommended as dietary supplement along with the chemotherapeutic agents against breast cancer.
Prolactin receptor targeting in breast and prostate cancers: New insights into an old challenge
2017, Pharmacology and Therapeutics
Citation Excerpt :
Paradigmatic observations and recently published data are discussed below. For further information and references to other original studies, the readers are invited to refer to the many reviews that have been published in the field (Arendt & Schuler, 2008; Clevenger et al., 2003, 2009; Fernandez, Touraine, & Goffin, 2010; Goffin & Touraine, 2015; Idelman, Jacobson, Tuttle, & Ben Jonathan, 2011; Lapensee & Ben Jonathan, 2010; O'Leary, Shea, & Schuler, 2015; Shemanko, 2016; Vonderhaar, 1998; Wagner & Rui, 2008). Animal studies involving genetically-induced mammary tumorigenesis (i.e. endogenous tumors) unanimously agree on the pro-tumorigenic role of PRLR signaling in vivo.
In the era of precision medicine, the identification of new targets is a constant challenge to improve cancer therapy. Preclinical investigations, epidemiological studies and analyses of tissue specimens from patients strongly support the contribution of prolactin receptor (PRLR) signaling to breast and prostate tumorigenesis and cancer progression. Although a clear causative link with mutations of the genes encoding prolactin or its receptor is lacking, increased PRLR signaling in these cancers can be assessed by the overexpression of cognate proteins and is often confirmed by over-activation of downstream signaling effectors. Nevertheless, the PRLR neutralizing antibody LFA102 tested recently in a Phase I trial in advanced, PRLR-positive prostate cancer and breast cancer patients failed to provide any clinical benefit. This underlines the need to better understand the actual impact of PRLR signaling on the progression of these cancers. Canonical PRLR-triggered signaling cascades include STAT5A/B, ERK1/2, PI3K/Akt, FAK and Src family kinases. Recent studies suggested that the nature and the outcome of PRLR signaling might be markedly different in breast than in prostate cancer. In the latter, like in many organs, PRLR/STAT5 signaling acts as a pro-tumorigenic pathway. In particular, it promotes the amplification of treatment-resistant prostate stem/progenitor cells, predicts early cancer recurrence and favors metastatic dissemination. In contrast, PRLR/STAT5 signaling was recently proposed to prevent breast cancer cell dissemination and to predict favorable clinical outcomes. While there is no evidence that pathways other than STAT5 are activated by prolactin in the prostate, these alternate signaling cascades may be primarily responsible for the pro-tumorigenic effects of prolactin in breast cancer. If these conclusions are confirmed in future studies, the therapeutic targeting of PRLR signaling in breast and prostate cancer may warrant the development of organ-specific strategies.
Antipsychotic-drug-induced hyperprolactinemia: Physiopathology, clinical features and guidance
2014, Encephale
L’hyperprolactinémie est un effet secondaire fréquent chez les patients traités par des antipsychotiques. Tous n’ont cependant pas le même potentiel hyperprolactinémiant. La fréquence des signes cliniques est le plus souvent corrélée à l’élévation de la prolactinémie mais l’hyperprolactinémie est parfois asymptomatique. Les manifestations cliniques relèvent principalement de troubles sexuels, de troubles du cycle menstruel et de galactorrhée, en plus d’effets à long terme. Ces signes ne sont pas toujours évoqués par les patients ce qui aboutit à une sous-estimation de la prévalence des hyperprolactinémies. Une revue de la littérature nous permet de proposer un bilan préthérapeutique. Le suivi en cours de traitement a, quant à lui, fait l’objet de recommandations par un groupe international d’experts en psychiatrie, médecine, toxicologie et pharmacologie qui conseille à la fois une surveillance clinique et biologique. Une conduite à tenir en cas d’hyperprolactinémie chez un patient sous antipsychotique est également décrite.
Hyperprolactinemia is a frequent but neglected adverse effect observed in patients treated with antipsychotic-drugs. In this review, we summarize its physiopathogenetic mechanism, its clinical manifestations in men and women, and the way to manage it.
Prolactin is a hormone secreted by lactotroph cells in the anterior pituitary. Its synthesis and release are under the control of peptides, steroids and neurotransmitters. The main inhibitory regulation is made by dopamine, which binds dopamine receptors D2 on the membrane of lactotroph cells. Antipsychotic-drugs block these receptors and thus remove the inhibitory effect of dopamine on prolactin secretion. All antipsychotic-drugs block D2 receptors and all can induce hyperprolactinemia. Nonetheless, it seems that the faster the antipsychotic-drug dissociates from D2 receptors, the lesser the increase of prolactin in the plasma. Another way to explain hyperprolactinemia is the ability of antipsychotic-drugs to cross the blood-brain barrier. The role of their metabolites should also be considered. For these reasons, one can distinguish prolactin-raising (conventional neuroleptics, amisulpride, risperidone) and prolactin-sparing (clozapine, aripiprazole, olanzapine) antipsychotics. An English study showed that 18% of men and 47% of women treated with antipsychotics for severe mental illness had a prolactin level above the normal range. Hyperprolactinemia is in fact more frequent in women than in men. Sometimes it is asymptomatic, but the higher the prolactin level is, the more patients have clinical manifestations. Some symptoms are due to the hypogonadism caused by prolactin, which disturbs hypothalamic-pituitary axis function, and others are due to direct effects on target tissues. Consequently, patients can suffer from sexual dysfunction, infertility, amenorrhea, gynecomastia or galactorrhoea. Data suggest that these symptoms are common, but patients don’t mention them spontaneously and clinicians underestimate their prevalence. In the long-term, hypogonadism involves a premature bone loss in men and women. Klibanski and colleagues showed that this loss is significant only in women with hyperprolactinemia associated with amenorrhea. That suggests that prolactin is not directly responsible for this clinical feature. Nevertheless, prolactin seems to be involved in the development of breast cancer, but its role is unclear for prostate cancer.
Our review promotes a check-up before beginning a treatment with antipsychotic agents. First, a baseline prolactin level should be measured. It should also include the research on previous treatment with antipsychotic-drugs and the assessment of adverse effects suggestive of hyperprolactinemia. Questioning should finally look for any contra-indication to antipsychotics. Monitoring during antipsychotic treatment has been studied by a group of international experts in psychiatry, medicine, toxicology and pharmacy who made a critical review of clinical guidance on hyperprolactinemia. Experts notify that it is important to check whether patients have any sexual dysfunction, such as loss of libido or menstrual irregularity, and galactorrhoea. Prolactin level should also be controlled after three months of stable dose treatment, or if any clinical feature of hyperprolactinemia appears. If a patient prescribed antipsychotic-drugs has a confirmed prolactin level above the normal range, it is necessary to exclude other causes of hyperprolactinemia. If antipsychotics are really involved, the management should be adapted with the prolactin level and the patient him/herself. To summarize, clinicians can decrease the dose of the antipsychotic or switch to a prolactin-sparing drug. Oral contraceptives can be added whether to prevent pregnancy or to prevent bone loss and osteoporosis. Finally, experts recommend reserving dopamine agonists to treat antipsychotic-induced hyperprolactinemia in very exceptional circumstances as it can worsen the mental illness.
Prolactin: An emerging force along the cutaneous-endocrine axis
2010, Trends in Endocrinology and Metabolism
Citation Excerpt :
That the skin produces PRL is not surprising, considering one of the defining features of mammals, the mammary gland, is an epidermal derivative developmentally related to sweat glands [6], whose epithelium is an important extrapituitary site of PRL expression [6]. The major regulatory role of PRL in mammary gland development, growth and function [7] and its potential role in mammary tumorigenesis [8], have long raised questions about its role in skin biology and pathology [9], including whether PRL might also regulate the second defining skin feature of mammals, the hair follicle (HF). PRL, whose gene is located on chromosome 6 in humans [10], is primarily produced under inhibitory dopaminergic control in the anterior pituitary gland [11].
Prolactin (PRL), one of the most diverse regulators in mammalian biology, is produced in both human skin and hair follicles. Important advances in our understanding of the intracutaneous regulation and functions of PRL have recently been made using the serum-free skin and hair follicle organ culture technique. Given that human skin is the largest peripheral endocrine organ and a key interface between the endocrine, nervous and immune systems, a detailed understanding of PRL in the cutaneous context promises to have far-reaching implications beyond the skin. The current review presents a timely cutaneous perspective on the production, regulation and functions of PRL and summarizes the key questions facing extrapituitary PRL research in general and cutaneous PRL research in particular.
Complex prolactin crosstalk in breast cancer: New therapeutic implications
2009, Molecular and Cellular Endocrinology
The contributions of prolactin (PRL) to breast cancer are becoming increasingly recognized. To better understand the role for PRL in this disease, its interactions with other oncogenic growth factors and hormones must be characterized. Here, we review our current understanding of PRL crosstalk with other mammary oncogenic factors, including estrogen, epidermal growth factor (EGF) family members, and insulin-like growth factor-I (IGF-I). The ability of PRL to potentiate the actions of these targets of highly successful endocrine and molecular therapies suggests that PRL and/or its receptor (PRLR) may be an attractive therapeutic target(s). We discuss the potential benefit of PRL/PRLR-targeted therapy in combination with established therapies and implications for de novo and acquired resistance to treatment.
Estrogen stimulates transcription from the human prolactin distal promoter through AP1 and estrogen responsive elements in T47D human breast cancer cells
2008, Molecular and Cellular Endocrinology
Human prolactin (hPRL) is a pleiotropic and versatile hormone that exercises more than 300 biological activities through binding to its cognate receptors. Recently, multiple studies have implicated hPRL in the development of human breast cancer. As a target of hPRL, both normal and neoplastic human breast cells also synthesize and secrete hPRL, which therefore establishes an autocrine/paracrine action loop in the mammary gland. In contrast to the extensive studies of regulation of hPRL expression in the pituitary gland, regulation of hPRL in mammary tissue and human breast cancer cells has not been extensively addressed. Extrapituitary PRL expression is primarily regulated by a distal promoter located 5.8 kb upstream to the pituitary promoter. As a result of alternative promoter usage, extrapituitary PRL is regulated by different signalling pathways and different hormones, cytokines or neuropeptides compared to regulation in the pituitary. Here, we present evidence that shows estrogen directly induces hPRL gene expression in T47D human breast cancer cells. We have identified a functional, non-canonical estrogen responsive element (ERE) and an AP1 site located in the hPRL distal promoter. Gel shift and chromatin immunoprecipitation assays demonstrated that both estrogen receptor (ER)α and ERβ directly bind to the ERE. However, only ERα interacts with AP1 proteins that bind to the AP1 site in the hPRL distal promoter. Promoter–reporter gene studies demonstrate that both ERE and AP1 sites are required for full induction of the promoter activity by estradiol. Our studies suggest that the interactions between estrogens, ERs, the ERE and AP1 transcription factors in regulation of autocrine/paracrine PRL in the human breast may be critical for oncogenesis and may contribute to progression of breast cancer.

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Prolactin: The Forgotten Hormone of Human Breast Cancer

Abstract

Introduction

Section snippets

Receptor Forms

Prolactin as Mitogen in Vivo

Serum Prolactin Levels in Breast Cancer Patients

Conclusion

Eur. J. Cancer

Exp. Cell Res.

Mol. Cell. Endocrinol.

Eur. J. Cancer Clin. Oncol.

J. Steroid Biochem.

Cancer Lett.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Pharmacol. Ther.

J. Biol. Chem.

Rec. Prog. Hormone Res.

Cell

Cell

Mol. Cell. Endocrinol.

Eur. J. Cancer Clin. Oncol.

J. Biol. Chem.

J. Invest. Dermatol.

Mol. Cell. Endocrinol.

Biochem. Biophys. Res. Commun.

J. Steroid Biochem.

Biochem. Biophys. Res. Commun.

Mol. Cell. Endocrinol.

Trends Endocrinol. Metab.

Eur. J. Cancer Clin. Oncol.

Highly specific sites of prolactin binding in benign and malignant breast disease

Indian J. Exp. Biol.

The Nb2 form of prolactin receptor is able to activate a milk protein gene promoter

Mol. Endocrinol.

Differential regulation of expression of three transforming growth factor β species in human breast cancer cell lines by estradiol

Cancer Res.

Transforming growth factor βpotential autocrine growth inhibitor of estrogen receptor-negative human breast cancer cells

Cancer Res.

Serum levels of insulin-like growth factor-I in operable breast cancer in relation to the main prognostic variables and their perioperative changes in relation to those of prolactin

Tumori

Extrapituitary prolactindistribution, regulation, functions, and clinical aspects

Endocr. Rev.

The short form of the prolactin (PRL) receptor silences PRL induction of the β-casein gene promoter

Mol. Endocrinol.

Role of serum in prolactin responsiveness of MCF-7 human breast cancer cells in long term tissue culture

Cancer Res.

Antiestrogen inhibition of prolactin induced growth of the Nb2 rat lymphoma cell line

Cancer Res.

Tamoxifen inhibition of prolactin action in the mouse mammary gland

Endocrinology

Induction of transforming growth factor β1 in human breast cancer in vivo following tamoxifen treatment

Cancer Res.

Tamoxifen induces TGF-β1 activity and apoptosis of human MCF-7 breast cancer cells in vitro

J. Cell. Biochem.

Regulation of IL-2-driven T-lymphocyte proliferation by prolactin

Proc. Natl. Acad. Sci. USA

Expression of prolactin and prolactin receptor in human breast carcinoma

Am. J. Pathol.

Histology and cytometrics in human breast cancers assayed for the presence of prolactin receptors

Tumori

Anti-oestrogens induce the secretion of active transforming growth factor beta from human fetal fibroblasts

Br. J. Cancer

Transduction of prolactin’s growth signal through both the long and short forms of the prolactin receptor

Mol. Endocrinol.

Characteristics of the antilactogen binding site in mammary gland membranes

Mol. Cell. Endocrinol.

Tamoxifen as an antilactogen in human breast cancer cells

Prolactin receptor does not correlate with oestrogen and progesterone receptors in primary breast cancer and lacks prognostic significance. Ten years results of the Naples adjuvant (GUN) study

Br. J. Cancer

Prolactin stimulation of protein kinase C in isolated mouse mammary gland nuclei

Horm. Metab. Res.

Rational design of potent antagonists to the human growth hormone receptor

Science

Nonpituitary human prolactin gene transcription is independent of pit-1 and differentially controlled in lymphocytes and in endometrial stroma

Mol. Endocrinol.

Prolactin synthesis and secretion by human breast cancer cells

Cancer Res.