Accepted Manuscript Review Autocrine/paracrine roles of extrapituitary growth hormone and prolactin in health and disease: an overview Steve Harvey, Carlos G. Martínez-Moreno, Maricela Luna, Carlos Arámburo PII: DOI: Reference:

S0016-6480(14)00423-7 http://dx.doi.org/10.1016/j.ygcen.2014.11.004 YGCEN 11979

To appear in:

General and Comparative Endocrinology

Please cite this article as: Harvey, S., Martínez-Moreno, C.G., Luna, M., Arámburo, C., Autocrine/paracrine roles of extrapituitary growth hormone and prolactin in health and disease: an overview, General and Comparative Endocrinology (2014), doi: http://dx.doi.org/10.1016/j.ygcen.2014.11.004

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Autocrine/paracrine roles of extrapituitary growth hormone and prolactin in health and disease: an overview

Steve Harvey*a, Carlos G. Martínez-Morenoa, Maricela Lunab, Carlos Arámburob

a

b

Department of Physiology, University of Alberta, Edmonton, T6G 2H7, Canada Departamento de Neurobiología, Celular y Molecular Instituto de Neurobiología, Universidad Nacional Autónoma de México, Querétaro, Qro., 76230, México

*To whom correspondence should be addressed: Dr. Steve Harvey Department of Physiology 7-41 Medical Sciences Building University of Alberta Edmonton, T6G 2H7 Tel: 1 780 492-2809 Fax: 1 780 492-3956 Email: [email protected]

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Abstract Growth hormone (GH) and prolactin (PRL) are both endocrines that are synthesized and released from the pituitary gland into systemic circulation. Both are therefore hormones and both have numerous physiological roles mediated through a myriad of target sites and both have pathophysiological consequences when present in excess or deficiency. GH or PRL gene expression is not, however, confined to the anterior pituitary gland and it occurs widely in many of their central and peripheral sites of action. This may reflect “leaky gene” phenomena and the fact that all cells have the potential to express every gene that is present in their genome. However, the presence of GH or PRL receptors in these extrapituitary sites of GH and PRL production suggests that they are autocrine or paracrine sites of GH and PRL action. These local actions often occur prior to the ontogeny of pituitary somatotrophs and lactotrophs and they may complement or differ from the roles of their pituitary counterparts. Many of these local actions are also of physiological significance, since they are impaired by a blockade of local GH or PRL production or by an antagonism of local GH or PRL action. These local actions may also be of pathophysiological significance, since autocrine or paracrine actions of GH and PRL are thought to be causally involved in a number of disease states, particularly in cancer. Autocrine GH for instance, is thought to be more oncogenic than pituitary GH and selective targeting of the autocrine moiety may provide a therapeutic approach to prevent tumor progression. In summary, GH and PRL are not just endocrine hormones, as they have autocrine and/or paracrine roles in health and disease.

Key words: Growth hormone; prolactin; pituitary; autocrine; paracrine

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1. Introduction Growth hormone (GH) and prolactin are both endocrines produced by the anterior pituitary gland and both have numerous physiological roles, in target sites that are almost ubiquitous. GH and prolactin are also produced within many of these target sites, in which they have autocrine or paracrine actions locally (Ben-Jonathan et al., 1996, 2013; Harvey, 2010; Harvey et al., 2012).

These local roles are of both physiological and pathophysiological

significance, as demonstrated by blocking their extrapituitary production or local action. The functional roles of extrapituitary GH and prolactin in health and disease is an emerging concept and the focus of this brief review.

2. Extrapituitary pituitary hormones While most hormones are expressed in specific endocrine glands, all cells have the potential to express every gene present in their genome. This may thus account for the ectopic expression of some hormones in “aberrant” locations, including the extrapituitary production of anterior pituitary hormones. The anterior pituitary gland is the main source of GH, prolactin, luteinizing hormone (LH), follicle-stimulating hormone (FSH), thyrotropin (TSH) and adrenocorticotropin (ACTH) found in peripheral circulation, since the concentrations of these hormones decline or are abolished following hypophysectomy (Harvey et al., 2012). The anterior pituitary is not, however, the only site in which the genes for these hormones are expressed.

Indeed, the

extrapituitary production of all of these hormones has been demonstrated in neural, immune, reproductive and alimentary tissues (Harvey et al., 2012). In most cases the contribution of the extrapituitary sources to the hormone concentrations in plasma is low, although their

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hypersecretion can mimic pituitary pathologies, such as acromegaly, hyperprolactinemia, hyperthyroidism, hypergonadism and Cushing’s syndrome (Harvey et al., 2012). Some of the actions of these extrapituitary pituitary hormones therefore complement the endocrine actions of their pituitary counterparts, although other local autocrine or paracrine roles, are likely to be related to tissue growth or differentiation (Sanders and Harvey, 2008). These local roles may be of particular importance in early embryonic or fetal development, before the acquisition of their classical endocrine roles, since extrapituitary hormones are produced in early development prior to the ontogeny of the pituitary gland (Harvey et al., 2012). Extrapituitary production of pituitary hormones may also be a cause or consequence of abnormal (tumorous) development and has often been associated with tumor progression. extrapituitary

production

of

pituitary

hormones

may

thus

have

The widespread physiological

or

pathophysiological relevance. 3. Extrapituitary growth hormone: distribution The widespread distribution of GH in extrapituitrary tissues was comprehensively reviewed four years ago (Harvey, 2010). Its presence was determined in neural tissues (in the brain and neural retina), in immune tissues (primary and secondary), in reproductive tissues (ovarian, uterine, mammary, placental, testicular and prostate), in gastrointestinal tissues (hepatic, pancreatic, salivary, alimentary tract), in skeletal and dental tissues, in integumentary tissue (skin), in muscular tissue, in cardiovascular tissue, and in respiratory tissue (lungs and gills). It is also abundant and widespread in embryonic tissues, in which it is expressed before its ontogenic appearance in pituitary somatotrophs (Harvey and Baudet, 2014). “Aberrant” GH expression is also a characteristic of many tissues undergoing neoplastic transformation, particularly the induction of breast and prostate cancer.

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4. Extrapituitary growth hormone: functional relevance The functional relevance of extrapituitary GH in autocrine or paracrine regulation has been demonstrated in studies in which endogenous GH production is blocked by siRNA’s (eg. Baudet et al., 2009, reducing neurite outgrowths and Sanders et al., 2010, increasing cell death). GH antisense oligonucleotides may similarly block endogenous GH production, which has been correlated with reduced neovascularization (Wilkinson-Berka et al., 2007), reduced cell proliferation (Weigent et al., 1991) and alterations in the tissue proteome (Beyea et al., 2009). Blocking endogenous GH action by immunoneutralization has also been correlated with increased cell death (Sanders et al., 2005, 2006), with reduced cell proliferation (Sabharwal and Varma, 1996; Markham and Kaye, 2003) and with abnormal cellular differentiation (Nguyen et al., 1996; Turnley et al., 2002). It has also been shown to reduce the expression of IGF-1 (insulin-like growth factor-1), a marker of GH action (Baxter et al., 1991). Blocking endogenous GH action using a GH receptor (GHR) antagonist has similarly been associated with increased cell death (Jeay et al., 2000) and with a reduced ability to stimulate cytokine production in immune cells (Malarkey et al., 2002). Blocking the endogenous secretion of GH, using somatostatin (SRIF), a GH release-inhibitory hormone, also results in an impairment of cellular (neural) differentiation (Turnley et al 2002). Functional autocrine/paracrine actions of endogenous GH have also been demonstrated by the induced expression of the GH gene in extrapituitary tissues. For instance, the expression of bovine GH in the CNS of mice has been shown to induce hyperphagia-induced obesity and appropriately, to increase the hypothalamic expression of the neuropeptide Y and agouti-related protein (Bohlooly et al., 2005). Similarly, the expression of human (h) GH in the cerebral cortex

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of mice is correlated with the induction of dwarfism, as a result of increased hypothalamic SRIF transcription and reduced GH-releasing hormone (GHRH) expression (Hollingshead et al., 1989). hGH expression in the GHRH neurons of the rat hypothalamus similarly increases SRIF transcription and reduces GHRH (Pellegrini et al., 1997) and similarly induces dwarfism (Flavell et al., 1996). Dwarfism is also induced in rats after hGH is expressed in the vasopressin neurons of their hypothalami (Wells et al., 2003). Functional autocrine/paracrine actions of endogenous extrapituitary GH have also been demonstrated during early development (Harvey and Baudet, 2014). Before the ontogeny of the pituitary gland, endogenous GH increased the formation of balstocysts in two-cell-stage mouse embryos, since this action was blocked by specific GHR antibodies (Fukaya et al., 1998). The addition of exogenous GH to two-cell mouse preimplantation embryos was similarly shown to increase the number of cells in the trophectoderm (Markham and Kaye, 2003). The functional importance of extrapituitary GH for embryonic growth was also demonstrated by the loss of sprouting neurites and the reduction in neurite size when endogenous GH in chick embryonic retinal ganglion cells (RGC’s) was reduced by siRNA knockdown (Baudet et al., 2009), which also reduced RGC cell survival during development (Baudet et al., 2009; Sanders et al., 2010, 2011). The immunoneutralization of endogenous GH in chick embryo RGC’s similarly resulted in cell death (Sanders et al., 2005, 2006, 2008, 2009), as also induced by GH antibodies in cerebellar neurons of chicken embryos (Alba-Betancourt et al., 2013). The importance of extrapituitary GH signaling in the chicken embryo is also demonstrated by the abundance and widespread expression of a specific GH-response gene (GHRG), GHRG-1, in central and peripheral tissues of 8-day old embryos (Harvey et al., 2001). GHRG-1 is a marker of GH action in chickens and its presence prior to somatotroph ontogeny (at approximately embryonic day 15;

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Harvey and Baudet, 2014) is a functional reflection of extrapituitary GH expression in the early chick embryo. Extrapituitary GH is also functional in the development of the mammalian fetus, as shown by the finding that the immunoneutralization of endogenous GH impaired the differentiation of the Wolffian duct in fetal rats, by a mechanism that was overcome by exogenous GH (Nguyen et al., 1996).

5. Extrapituitary growth hormone: pathophysiological roles. GH has numerous roles as a cytokine and is produced by many immune tissues and immune cells (Chappel, 1999; Waters et al., 1991, Jeay et al., 2002). Not surprisingly, it has therefore been implicated in the etiology of autoimmune pathologies (Jeay at al., 2002), including arthritis. Local GH production is thought to contribute to both osteoarthritis and rheumatoid arthritis, since synovial fluid GH levels are higher than blood GH levels in both disease states (Denko and Malamud, 2005) and GH immunoreactivity is present in articular cartilage (Costa et al., 1993). This possibility is supported by the finding that the overexpression of bovine GH in transgenic mice results in lesions of the articular cartilage that are consistent with that described in osteoarthritis (Fernandez-Criado et al., 2004). Moreover, the efficacy of exogenous SRIF in reducing joint pain and synovial thickness (Silveri et al., 1994, 1997; Coarti et al., 1995) might reflect its inhibition of local GH production. Extrapituitary GH expression has also been correlated in tumor development, in which autocrine GH has been implicated in neoplastic transformation (Perry et al., 2006). Autocrine GH is thought to enhance cell proliferation, protect against apoptosis and to promote aberrant morphogenesis. In breast cancer, this is in marked contrast to exogenous GH, which does not induce tumor formation, nor protect cancerous cells against the apoptosis that results from serum

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withdrawal (Kaulsay et al., 2000, 2001). This selective effect of endogenous GH may reflect the greater augmentation of STAT5-mediated gene transcription induced by autocrine GH compared with exogenous GH (Kaulsay et al., 1999). Autocrine GH similarly affects a number of other genes that are differentially regulated by exogenous GH (Mertani et al., 2001; Xu et al., 2005). One of these genes is CHOP (P38 MAP kinase specific), which is up-regulated by autocrine GH in cancerous mammary cells. Another is the p53-regulated placental transforming growth factor (PTGH) – β gene, which is transcriptionally repressed, inhibiting its ability to induce cell cycle arrest and apoptosis (Graichen et al., 2002). Another mechanism through which autocrine GH may induce breast carcinoma is by increasing tumor blood micro-vessel density, by selectively increasing VEGF (vascular endothelial growth factor) expression (Brunet-Dunand et al., 2009). Other differentially regulated genes include trefoil factors (TFFs), that promote cell survival, anchorage-independent growth, motifity and oncogenic transformation (Perry et al., 2008a, b). The differential actions of endogenous and exogenous GH may reflect differences in the cellular localization of the activated GHR’s, since endogenous GH may act at intracellular receptors not readily accessible to exogenous GH. Indeed, autocrine GH binds to the GHR receptor immediately after synthesis in the endoplasmic reticulum and the hormone-receptor complex is then inserted into the plasma membrane, where exogenous GH is unable to bind (van den Eijnden and Strous, 2007). Autocrine GH has similarly been shown to sequester GHR in the Golgi and endoplasmic reticulum of prostate cancer cells, in which it promotes proliferation and cell survival (Nakonechnaya et al., 2013). Autocrine GH is also thought to act through nuclear receptors and nuclear GHRs are markers of tumorogenesis in cancerous cells (Perry et al., 2006; Conway-Campbell et al., 2007). Nuclear targeting of the GHR is thought to induce cell cycle

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proliferation and a dysregulated proliferative arrest through increased expression of the proliferation-related proteins Survivin and Mybbp (Conway-Campbell et al., 2007). As GH is thought to induce cancer through acting through the GHR, GHR antagonists have been proposed for both imaging and therapeutic applications. For instance, GH-conjugated to a carboxylated nanodimond has been used to induce cell death in a non-small-cell lung cancer cell line (Chu et al., 2014) and this laser-mediated cancer-targeting platform may be widely used in the future. Pegvisomant, a specific GHR antagonist, has also been proposed as treatment for selected types of cancer (Kopchick et al., 2014). Another putative therapeutic approach is the siRNA inhibition of the GHR, which has recently been shown to be effective in the treatment of colon cancer progression in an experimental (mouse) cell line (Zhou et al., 2013) and in canine mammary carcinoma cell line (Pawlowski et et al., 2012). In summary, local autocrine or paracrine actions of extrapituitary GH have functional implications in both health and disease.

6. Extrapituitary prolactin: distribution The existence of extrapituitary prolactin sources was first realized by the discovery of lactogenic activity in the plasma of hypophysectomized rats, which increased in activity over time (Nagy and Berezi, 1991). The concentration of prolactin in CSF is similarly independent of hypophysectomy (Barbanel et al., 1986). Since then, prolactin has now been found in many extrapituitary tissues, as first reviewed by Ben Jonathan et al. (1996) and more recently by Harvey at al. (2012) and by Marano and Ben-Jonathan (2014). It has, for instance been located in a variety of reproductive tissues (in ovaries, the deciduas, placenta, mammary glands, testes, prostate and germ cells), immune tissues (leucocytes, bone marrow, thymus, spleen, tonsils,

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lymph nodes), neural tissues (brain and spinal cord, in sense organs and vitreous fluid), integumentary tissues (skin, sweat glands, sebaceous glands, hair and hair follicles) and other locations (in lachrymal glands, kidneys, in adipose and in blood endothelial cells) (see Table 1). These studies include those that show the presence of prolactin mRNA (eg. by in situ in the neuralretina; Aranda et al., 2005; by RT-PCR in hair follicles, Foitzik et al., 2006; by RT-PCR in ovarian follicles, Phelps et al., 2003) and those that show the presence of immunoreactive proteins (eg. by immunohistochemistry and western blotting in capillary endothelial cells, Ochoa et al., 2001; by radioimmunoassay in adipose tissue explants, Hugo et al., 2008).

7. Extrapituitary prolactin: characteristics The expression of the prolactin gene in extrapituitary tissues may be cell or tissue specific (Marano and Ben-Jonathan, 2014). Specifically, the extrapituitary prolactin transcript differs from pituitary prolactin in that it has an additional 150 bp sequence, due to the presence of a 5’ non coding exon (exon 1a), located 5.8 kb upstream of the extrapituitary prolactin start site, which is driven by a superdistal promoter (Gerlo et al., 2006; Zinger et al., 2003), whereas the pituitary prolactin gene is driven by a proximal promoter. The expressed proteins of both genes are, however, identical in terms of primary, secondary and tertiary structure and in receptor binding (Goffin et al., 2002). The expression of the pituitary prolactin gene is activated by the Pit-1 transcription factor and suppressed in response to dopamine. In contrast, the promoter of extrapituitary prolactin is largely independent of Pit-1, although the presence of Pit-1 mRNA in the kidney was found to correlate with localization of the prolactin transcript (Sakai et al., 1999). Pit-1, which is lacking exon 1, also activates the extrapituitary prolactin gene in mouse spermatids and spermatocytes

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(Maeda et al., 2012). Extrapituitary prolactin was also considered to be dopamine-independent, as dopamine did not inhibit prolactin production in the decidua (Golander et al., 1979), nor amniotic fluid (Lehtovirta and Ranta, 1981) or in human skin (Langan et al., 2013). However, human adipocytes express functional dopamine receptors and dopamine stimulation inhibits prolactin gene expression in these sites (Borcherding et al., 2011). The regulation of the extrapituitary prolactin gene is thus likely to be tissue specific (Langan et al., 2012; Merano and Ben-Jonathan, 2014). The expression of the pituitary prolactin gene is stimulated by thyrotropin-releasing hormone and estrogen and both of these factors also stimulate the production of extrapituitary prolactin in human skin and cultured hair follicles (Langan et al., 2010). Estrogen similarly stimulates prolactin production in the rat brain (Torner et al., 1999), although it does not stimulate prolactin release from glandular breast tissue not breast adipose tissue (Zinger et al., 2003). In contrast with pituitary prolactin, substance P, TNF (tumor necrosis factor) α and interferon (IFN) γ have also been found to be novel modulators of prolactin expression in human skin (substance P and TNF α as inhibitors and IFN γ as a stimulator) (Langan et al., 2013). The extrapituitary production of prolactin by human decidual cells is thought to be regulated by a novel autocrine/paracrine system between the placenta, the fetal membranes and the decidua. This includes a 35-45 kDa decidual protein with inhibitory activity, although arachidonic acid, interferon γ and lipocortin 1 have also been identified as local inhibitory factors whist a 23.5 kDa decidual protein, IGF-1, insulin and relaxin have been identified as stimulators of decidual prolactin expression (Handwerger et al., 1991). The expression of decidual prolactin is also controlled by many cytokines, transcription factors and signaling peptides that indirectly act though regulatory pathways or by binding directly to control elements within the decidual

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prolactin promoter (Marano and Ben-Jonathan, 2014). There is, for instance, a cAMP response element (CRE) in the promoter, although cAMP additionally activates the prolactin gene indirectly through sequences outside the CRE 1 (Marano and Ben-Jonathan, 2014). The transcription factors Jun D and Fos-related antigen (Fra-2) have also been shown to bind to an enhancer region within the superdistal promoter, which increases decidual prolactin production (Watanabe et al., 2001). The transcription factor Ets-1 is also an enhancer of decidual prolactin expression (Brar et al., 2002), as is Nur77 (Jiang et al., 2011), which increases decidualization and the expression of prolactin induced by 8-br-cAMP and medroxyprogesterone acetate (MPA). Prolactin production by human fibroblasts is, however, not increased by MPA, nor by estrogen, although both are stimulatory in the presence of prostaglandin E2 (Richards and Hartman, 1996). Other factors regulating prolactin expression include calcitrol, which increases prolactin production by resting mononuclear cells, although it inhibits prolactin production by activated immune cells (Diaz et al., 2011), in contrast progesterone suppressed prolactin release from glandular breast tissue, without affecting prolactin release from breast adipose tissue (Zinger et al., 2003).

8. Extrapituitary prolactin: functional relevance Pituitary prolactin’s main physiological roles are the stimulation of lactogenesis and galactopoesis, but it is thought to have >300 other actions that regulate reproduction, osmoregulation, intermediary metabolism and changes in immune and neural function (BoleFeysot et al., 1998; Goffin et al., 2002; Ignacak et al., 2012). The almost ubiquitous presence of prolactin receptors in extrapituitary sites of prolactin production suggests that some of these actions reflect local autocrine and paracrine roles of extrapituitary prolactin. The presence and

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abundance of prolactin in skin, for instance, has provided a novel perspective on prolactin’s roles in skin and hair physiology (Foitzik et al., 2006, 2009; Langan et al., 2009). Similarly, the finding of prolactin and its fragments in the cardiovascular system and discovery of their novel angiogenic and anti-angiogenic roles has lead to the conceptualization of a new class of regulators called vasoinhibins (Clapp et al., 1998; Goffin et al., 2002). Autocrine and paracrine actions of prolactin within the immune system are also known to complement the endocrine actions of pituitary prolactin in immune function but they also provide causal mechanisms for the induction of autoimmunity (Matera, 1996; De Bellis et al., 2005; Mendez et al., 2005). Many of these autocrine or paracrine pathways also activate signaling pathways that regulate cell proliferation, cell migration and cell death and they have therefore been implicated in the etiology and progression and treatment of cancer (Fernandez et al., 2010; Bernichtein et al., 2010; Musthuswamy, 2012). The functional importance of extrapituitary prolactin productions has been shown by studies that demonstrate biological actions after the immunoneutralization of endogenous prolactin (Table 2). For instance, brain capillary endothelial cells are known to express the prolactin gene and the prolactin-like activity of the translated proteins was shown by their ability to stimulate the proliferation of Nb2-cells when they were co-cultured with endothelial cells (Clapp et al., 1998). This was due to the local production of prolactin, since polyclonal and monoclonal prolactin antibodies were shown to inhibit basal and fibroblast growth factorstimulated growth of endothelial cells. Blocking endogenous prolactin activity in brain endothelial cells removes their endogenous pro-angiogenic acitivity (Yang et al., 2013), which is known to result from full-length monomer prolactin (Corbacho et al., 2002). In contrast, the 16 kDa fragment of prolactin is anti-angiogenic (Corbacho et al., 2002) and intravitreal injections of

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antibodies that are able to neutralize 16 kDa prolactin increases the numbers of blood vessels in the retina (Aranda et al., 2005). This action was specific to the 16 kDa fragment, as prolactin antibodies unable to bind to the fragment were ineffective. Antibodies to prolactin also block autocrine actions of lymphocytes that result in lymphocyte activation and CD69 and CD154 expression and interferon secretion (Chavez-Rueda et al., 2005, 2007). Autocrine and paracrine actions of endogenous prolactin in human myometral and lecucomyoma cells that stimulate cell proliferation and similarly blocked by the immunoneutralization (Novak et al., 1999). Autocrine prolactin production in mammary epithelial cells is also required for the initiation of lactation, as this is blocked after treatment with an anti-prolactin antibody (Chen et al., 2012). Functional autocrine or paracrine actions of extrapituitary prolactin have also been demonstrated by siRNA or shRNA knockdown of endogenous prolactin gene expression. For instance, reduced prolactin expression blocks its pro-angiogenic action in human brain endothelial cells (Yang et al., 2013). Suppressing prolactin expression in the neural retina has also been shown to reduce the production of the 16 kDa cleaved prolactin fragment and to increase retinal neovascularization in rats (Aranda et al., 2005). The inhibition of in vivo prolactin translation in the zebra fish has also been found to cause multiple morphological defects during embryogenesis (Nguyen et al., 2008). Inhibition of prolactin gene expression in the mammary gland also impairs the inhibition of lactation, as does the blockade of the prolactin receptor (Chen et al., 2012). Research with prolactin receptor knockout mice has shown that prolactin directly regulates lobuloalveolar development and lactogenesis during pregnancy (Brisken et al., 1999). The stimulation of mammary epithelial growth is due to autocrine actions of mammary prolactin, as it is reduced after deletion of the mammary prolactin gene (Naylor et al., 2003). Knockdown

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of the prolactin receptor also reduces lymphocyte proliferation induced by autocrine prolactin production (Xu et al., 2010). Similarly, the increased proliferation of prostate cells has been shown to be induced by the autocrine production of prolactin and the pharmaceutical blockade of the prolactin receptor, using a specific antagonist (Delta 1-9G129R-hPRL), blocks this response (Dagvadorj et al., 2007). This same antagonist has also been shown to inhibit the decidualization of the human uterus that is induced by the autocrine actions of decidual prolactin (Eyal et al., 2007). Another prolactin receptor antagonist S179D, has also been found to be a potent antiangiogenic and anti-inflammatory agent for the treatment of prostate cancer and other angioproliferative disorders (Walker, 2006). A neutralizing monoclonal antibody against the prolactin receptor similarly blocks the autocrine prolactin-induced cell proliferation in breast cancer cells (Damiano et al., 2013). Functional roles of extrapituitary prolactin have also been demonstrated by its local overexpression. This was shown in cancerous mammary cell lines that were genetically engineered to overexpress human prolactin, which increased the expression of the estrogen receptor alpha and the cancer progression (Gutzman et al., 2004). The local overexpression of prolactin mice mammary glands similarly induces dramatic functional and morphological defects, including benign lesions (Manhes et al., 2006). Increased autocrine production of prolactin also occurs in rabbit lacrimal glands in response to an adenoviral vector, which results in physiological changes in lacrimal function (Wang et al., 2007). Finally, pharmacologically upregulating the expression of the prolactin receptor has shown this to activate prolactin signaling pathways that increase cellular proliferation (Oliviera-Ferrer et al., 2013). Prolactin and the prolactin receptor have also been well characterized in human deciduas, in which extrapituitary prolactin is thought to have autocrine/paracrine roles that are critical for

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blastocyst implantation and early pregnancy (Tanaka et al., 1996; Jabbour and Critchley, 2001). Indeed, null mutation of the prolactin receptor gene leads to female sterility due to severely compromised preimplantation development and impaired blastocyst formation (Binart et al., 2000). Prolactin is also produced and act in the extraorbital lacrimal gland, in which prolactin inhibits carbachol-induced peroxidase release. Prolactin might thus function as an autocrine/paracrine or exocrine in the lachrymal gland (Mircheff et al., 1992).

9. Extrapituitary prolactin: pathophysiological roles It is now well established that prolactin and its receptor are expressed in many types of cancer. Particularly breast and prostate cancer, although it may also participate in colorectal, gynecological, laryngeal and hepatocellular cancer (Levina et al., 2009; Sethi et al., 2012). The persistence of sustained serum levels of prolactin in patients post-hypophysectomy supports its extrapituitary origin (Clevenger and Plank, 1997), as does the detection of prolactin transcripts generated from the distal promoter (Shaw-Bruha et al., 1997). The relative importance of pituitary and extrapituitary prolactin in inducing breast cancer is, however, still controversial and disputed by a recent publication (Nitze et al., 2013). Autocrine/paracrine actions of prolactin are however thought to promote tumor progression. These actions are also thought to reflect the presence of a number of prolactin receptor isoforms in some cancers, including constitutively active receptor variants (Fernandez et al., 2010; Bernichtein et al., 2010) through which genomic and non-genomic signaling triggers an orchestrated pattern of gene expression that leads to tumor progression (Clevenger, 2003; Clevenger et al., 2003). These actions promote cell proliferation and migration and inhibit cell death (Chen et al., 2012; Muthuswamy, 2012).

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Blocking prolactin signaling by the use of specific prolactin receptor antagonists has therefore been proposed as a future therapeutic approach in the treatment of cancer (Tallet et al., 2008; Bernichtein et al., 2010; Fernandez et al., 2010). In addition to cancer, the presence of prolactin and its receptor in a number of extrapituitary tissues as implication in the etiology of autoimmune diseases (Mendez et al., 2005), especially as hyperprolactinemia is associated with systemic lupus erythematosus (SLE), Reiter’s disease, rheumatoid arthritis (RA), Hashimoto’s thyroditis, Addison’s disease, celiac disease, type 1 diabetes mellitus and multiple sclerosis (Chikanza, 1999; Jara et al., 2001; De Bellis et al., 2005). The production of prolactin in T-lymphocytes is for instance, much higher in patients with SLE than in control subjects. The incidence of SLE is also strongly correlated with a single nucleotide polymorphism (SNP) in the promoter region, since the disease is more prevalent in patients with a PRL-1149 G/T allele than in normal subjects (Stevens et al., 2001). Manipulating the production of lymphocyte prolactin (rather than pituitary prolactin) might therefore be a useful therapeutic approach in the treatment of this autoimmune disease. The increased production of prolactin by adipose tissue macrophages is similarly thought to be partially responsible for the correlation between prolactin oversecretion and obesity (Borcherding et al., 2011; Bouckenoughe et al., 2014) The production of prolactin by synovium infiltrating T-cells and fibroblast-like synovial cells has also been implicated in arthritis, in which prolactin, acting through is expressed receptor, stimulates the production of proinflammatory cytokines and collagenases (Nagafuchi et al., 1999). Inhibitors of prolactin release, such as bromocryptine, have therefore been proposed as local treatments for this autoimmune condition (Kokot et al., 2013). Interestingly, the same SNP polymorphism associated with SLE also occurs with increased frequency in mexican RA

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patients (Reyes-Castillo et al., 2003), although it is not correlated with the etiology of juvenile idiopathic arthritis (Donn et al., 2002) nor psoriatic arthritis (Stolfa et al., 2007). Psoriatic arthritis affects patients suffering from psoriasis, which is another dermatological condition in which the local production and action of prolactin may have pathological relevance (Foitik et al., 2009). In summary, extrapituitary prolactin, like extrapituitary GH, has functional importance in both health and disease.

Acknowledgments Supported by NSERC of Canada and CONACyT of Mexico (postdoctoral fellowship to CGMM, 208148).

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Table 1. Extrapituitary prolactin: distribution Tissue Reference Reproductive Tissue Ovaries (amniotic fluid/corpus luteum) Larrea et al., 1991; Shibaya et al., 2006; Erdmann et al., 2007 -Oocytes Yang et al., 1999 Decidua/uterus Eyal et al., 2007; Jiang et al., 2011; Emera et al., 2012; Kautz et al., 2014 Placenta Menzies et al., 2011 Mammary glands Le Provost et al., 1994; Iwasaka et al., 2000; Koizumi et al., 2003 Testes Untergasser et al., 1996 -Germ cells Maeda et al., 2012 -Leydig cells Ishida et al., 2010 Prostate Christensen et al., 2013 Immune Tissue Monocytes Leukocytes Bone marrow Thymus Spleen Tonsils Lymph nodes Neural Tissue Brain and -CSF -Vitreous humor -Aqueous humor

Cejkova et al., 2012; López-Rincón et al., 2013 Montgomery et al., 1992; Pellegrini et al., 1992; Gerlo et al., 2005 Delhase et al., 1991; Bellone et al., 1997 O’Neal et al., 1992; Wu et al., 1996 Horiguchi et al., 2004 Delhase et al., 1993 Wu et al., 1996 Chen et al., 2004; Torner et al., 2004; Zhang et al., 2004; Shiue et al., 2006 Jara et al., 1996 Duenas et al., 2004 Pleyer et al., 2001

Integumentary Tissue Skin Sweat glands Sebaceous gland Hair/hair follicles

Foitzik et al., 2009; Lanagan et al., 2013 Foitzik et al., 2009 Foitzik et al., 2009 Foitzik et al., 2009; Lanagan et al., 2010

Other Lachrimal glands Kidneys Adipose tissue

Wang et al., 2007 Sahai et al., 1999 Bouckenooghe et al., 2014; Carre and Binart, 2014;

Borcherding et al., 2011; Hugo et al., 2008 Blood endothelia Salivary glands

Wu et al., 1996; Endmann et al., 2007; Corbacho et al., 2000 Steinfield et al., 2000

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Table 2. Extrapituitary prolactin: functional autocrine/paracrine roles Manipulation Action Reference PRL antibodies ↑angiogenesis Yang et al., 2013 ↓angiogenesis/vasodilation Aranda et al., 2005 ↑cell differentiation Chen et al., 2012 ↑cell proliferation Clapp et al., 1998 ↑cell growth Nowack et al., 1999 PRL knockdown ↑angiogenesis Yang et al., 2013 ↓angiogenesis Aranda et al., 2005 ↑lymphocyte activation Chavez-Rueda et al., 2005 ↑organogenesis Nguyen et al., 2008 Receptor antagonism ↑cell viability Dagvadorj et al., 2007 ↑cell proliferation Ferraris et al., 2013 ↑cell proliferation Eyal et al., 2007 ↑keratin expression Ramot et al., 2010 Receptor knockout ↑cell proliferation Naylor et al., 2003 ↑cell proliferation Xu et al., 2010 ↑cell differentiation Chen et al., 2012 Receptor antibodies ↑cell proliferation Damiano et al., 2013 ↑cell proliferation Dagvadorj et al., 2007 Receptor overexpression ↑cell proliferation Oliveira-Ferrer et al., 2013 ↓cell differentiation Manhes et al., 2006

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GH and prolactin have autocrine or paracrine roles in extrapituitary sites of synthesis These roles have functional significance in health or disease GH and prolactin are not just pituitary endocrines but local growth factors