The major 23 kDa prolactin isoform exerts its action via a transmembrane receptor, prolactin receptor (PRL-R), which belongs to the class of haematopoietic cytokine receptors
Binding of prolactin to its predimerized receptor induces a conformational change in the receptor, which enables signal transduction
Hyperprolactinaemia causes hypogonadotropic hypogonadism by inhibiting kisspeptin-1 secretion, which in turn disrupts hypothalamic gonadotropin-releasing hormone I secretion
The first germline loss-of-function mutation in the gene that encodes PRL-R was reported in three sisters with familial idiopathic hyperprolactinaemia
The 16 kDa isoform of prolactin has antitumoral and antiangiogenic actions and is involved in peripartum cardiomyopathy
Prolactin is a hormone that is mainly secreted by lactotroph cells of the anterior pituitary gland, and is involved in many biological processes including lactation and reproduction. Animal models have provided insights into the biology of prolactin proteins and offer compelling evidence that the different prolactin isoforms each have independent biological functions. The major isoform, 23 kDa prolactin, acts via its membrane receptor, the prolactin receptor (PRL-R), which is a member of the haematopoietic cytokine superfamily and for which the mechanism of activation has been deciphered. The 16 kDa prolactin isoform is a cleavage product derived from native prolactin, which has received particular attention as a result of its newly described inhibitory effects on angiogenesis and tumorigenesis. The discovery of multiple extrapituitary sites of prolactin secretion also increases the range of known functions of this hormone. This Review summarizes current knowledge of the biology of prolactin and its receptor, as well as its physiological and pathological roles. We focus on the role of prolactin in human pathophysiology, particularly the discovery of the mechanism underlying infertility associated with hyperprolactinaemia and the identification of the first mutation in human PRLR.
Subscribe to Journal
Get full journal access for 1 year
only $17.75 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Nagano, M. & Kelly, P. A. Tissue distribution and regulation of rat prolactin receptor gene expression. Quantitative analysis by polymerase chain reaction. J. Biol. Chem. 269, 13337–13345 (1994).
Freemark, M., Driscoll, P., Maaskant, R., Petryk, A. & Kelly, P. A. Ontogenesis of prolactin receptors in the human fetus in early gestation. Implications for tissue differentiation and development. J. Clin. Invest. 99, 1107–1117 (1997).
Bole-Feysot, C., Goffin, V., Edery, M., Binart, N. & Kelly, P. A. Prolactin (PRL) and its receptor: actions, signal transduction pathways and phenotypes observed in PRL receptor knockout mice. Endocr. Rev. 19, 225–268 (1998).
Goffin, V., Binart, N., Touraine, P. & Kelly, P. A. Prolactin: the new biology of an old hormone. Annu. Rev. Physiol. 64, 47–67 (2002).
Ben-Jonathan, N., LaPensee, C. R. & LaPensee, E. W. What can we learn from rodents about prolactin in humans? Endocr. Rev. 29, 1–41 (2008).
Clapp, C., Aranda, J., González, C., Jeziorski, M. C. & Martínez de la Escalera, G. Vasoinhibins: endogenous regulators of angiogenesis and vascular function. Trends Endocrinol. Metab. 17, 301–307 (2006).
Truong, A. T. et al. Isolation and characterization of the human prolactin gene. EMBO J. 3, 429–437 (1984).
Hiraoka, Y. et al. A placenta-specific 5′ non-coding exon of human prolactin. Mol. Cell. Endocrinol. 75, 71–80 (1991).
Freeman, M. E., Kanyicska, B., Lerant, A. & Nagy, G. Prolactin: structure, function, and regulation of secretion. Physiol. Rev. 80, 1523–1631 (2000).
Horseman, N. D. & Yu-Lee, L. Y. Transcriptional regulation by the helix bundle peptide hormones: growth hormone, prolactin, and hematopoietic cytokines. Endocr. Rev. 15, 627–649 (1994).
Walker, A. M. S179D prolactin: antagonistic agony! Mol. Cell. Endocrinol. 276, 1–9 (2007).
Fahie-Wilson, M. & Smith, T. P. Determination of prolactin: the macroprolactin problem. Best Pract. Res. Clin. Endocrinol. Metab. 27, 725–742 (2013).
Suliman, A. M., Smith, T. P., Gibney, J. & McKenna, T. J. Frequent misdiagnosis and mismanagement of hyperprolactinemic patients before the introduction of macroprolactin screening: application of a new strict laboratory definition of macroprolactinemia. Clin. Chem. 49, 1504–1509 (2003).
Gibney, J., Smith, T. P. & McKenna, T. J. The impact on clinical practice of routine screening for macroprolactin. J. Clin. Endocrinol. Metab. 90, 3927–3932 (2005).
McKenna, T. J. Should macroprolactin be measured in all hyperprolactinaemic sera? Clin. Endocrinol. (Oxf.) 71, 466–469 (2009).
Clapp, C. & Weiner, R. I. A specific, high affinity, saturable binding site for the 16-kilodalton fragment of prolactin on capillary endothelial cells. Endocrinology 130, 1380–1386 (1992).
Macotela, Y. et al. Matrix metalloproteases from chondrocytes generate an antiangiogenic 16 kDa prolactin. J. Cell Sci. 119, 1790–1800 (2006).
Ochoa, A. et al. Expression of prolactin gene and secretion of prolactin by rat retinal capillary endothelial cells. Invest. Ophthalmol. Vis. Sci. 42, 1639–1645 (2001).
Hilfiker-Kleiner, D. et al. A cathepsin D-cleaved 16 kDa form of prolactin mediates postpartum cardiomyopathy. Cell 128, 589–600 (2007).
Lkhider, M., Castino, R., Bouguyon, E., Isidoro, C. & Ollivier-Bousquet, M. Cathepsin D released by lactating rat mammary epithelial cells is involved in prolactin cleavage under physiological conditions. J. Cell Sci. 117, 5155–5164 (2004).
Clapp, C., Martial, J. A., Guzman, R. C., Rentier-Delure, F. & Weiner, R. I. The 16-kilodalton N-terminal fragment of human prolactin is a potent inhibitor of angiogenesis. Endocrinology 133, 1292–1299 (1993).
Grattan, D. R. & Kokay, I. C. Prolactin: a pleiotropic neuroendocrine hormone. J. Neuroendocrinol. 20, 752–763 (2008).
Schuff, K. G. et al. Lack of prolactin receptor signaling in mice results in lactotroph proliferation and prolactinomas by dopamine-dependent and -independent mechanisms. J. Clin. Invest. 110, 973–981 (2002).
Marano, R. J. & Ben-Jonathan, N. Minireview: extrapituitary prolactin: an update on the distribution, regulation, and functions. Mol. Endocrinol. 28, 622–633 (2014).
Gellersen, B., Kempf, R., Telgmann, R. & DiMattia, G. E. Nonpituitary human prolactin gene transcription is independent of Pit-1 and differentially controlled in lymphocytes and in endometrial stroma. Mol. Endocrinol. 8, 356–373 (1994).
Peers, B. et al. Regulatory elements controlling pituitary-specific expression of the human prolactin gene. Mol. Cell. Biol. 10, 4690–4700 (1990).
Ben-Jonathan, N., Mershon, J. L., Allen, D. L. & Steinmetz, R. W. Extrapituitary prolactin: distribution, regulation, functions, and clinical aspects. Endocr. Rev. 17, 639–669 (1996).
Langan, E. A., Foitzik-Lau, K., Goffin, V., Ramot, Y. & Paus, R. Prolactin: an emerging force along the cutaneous-endocrine axis. Trends Endocrinol. Metab. 21, 569–577 (2010).
Brandebourg, T., Hugo, E. & Ben-Jonathan, N. Adipocyte prolactin: regulation of release and putative functions. Diabetes Obes. Metab. 9, 464–476 (2007).
Marano, R. J., Tickner, J. & Redmond, S. L. Prolactin expression in the cochlea of aged BALB/c mice is gender biased and correlates to loss of bone mineral density and hearing loss. PLoS ONE 8, e63952 (2013).
Chen, C.-C. et al. Autocrine prolactin induced by the Pten-Akt pathway is required for lactation initiation and provides a direct link between the Akt and Stat5 pathways. Genes Dev. 26, 2154–2168 (2012).
Dagil, R. et al. The WSXWS motif in cytokine receptors is a molecular switch involved in receptor activation: insight from structures of the prolactin receptor. Structure 20, 270–282 (2012).
Kelly, P. A., Djiane, J., Postel-Vinay, M. C. & Edery, M. The prolactin/growth hormone receptor family. Endocr. Rev. 12, 235–251 (1991).
Lebrun, J. J., Ali, S., Sofer, L., Ullrich, A. & Kelly, P. A. Prolactin-induced proliferation of Nb2 cells involves tyrosine phosphorylation of the prolactin receptor and its associated tyrosine kinase JAK2. J. Biol. Chem. 269, 14021–14026 (1994).
Tanner, J. W., Chen, W., Young, R. L., Longmore, G. D. & Shaw, A. S. The conserved Box 1 motif of cytokine receptors is required for association with JAK kinases. J. Biol. Chem. 270, 6523–6530 (1995).
Binart, N., Bachelot, A. & Bouilly, J. Impact of prolactin receptor isoforms on reproduction. Trends Endocrinol. Metab. 21, 362–368 (2010).
Arden, K. C., Boutin, J. M., Djiane, J., Kelly, P. A. & Cavenee, W. K. The receptors for prolactin and growth hormone are localized in the same region of human chromosome 5. Cytogenet. Cell Genet. 53, 161–165 (1990).
Barker, C. S. et al. Activation of the prolactin receptor gene by promoter insertion in a Moloney murine leukemia virus-induced rat thymoma. J. Virol. 66, 6763–6768 (1992).
Hu, Z.-Z., Zhuang, L., Meng, J., Leondires, M. & Dufau, M. L. The human prolactin receptor gene structure and alternative promoter utilization: the generic promoter hPIII and a novel human promoter hPN . J. Clin. Endocrinol. Metab. 84, 1153–1156 (1999).
Hu, Z. Z., Meng, J. & Dufau, M. L. Isolation and characterization of two novel forms of the human prolactin receptor generated by alternative splicing of a newly identified exon 11. J. Biol. Chem. 276, 41086–41094 (2001).
Kline, J. B., Roehrs, H. & Clevenger, C. V. Functional characterization of the intermediate isoform of the human prolactin receptor. J. Biol. Chem. 274, 35461–35468 (1999).
Trott, J. F., Hovey, R. C., Koduri, S. & Vonderhaar, B. K. Multiple new isoforms of the human prolactin receptor gene. Adv. Exp. Med. Biol. 554, 495–499 (2004).
Postel-Vinay, M. C., Belair, L., Kayser, C., Kelly, P. A. & Djiane, J. Identification of prolactin and growth hormone binding proteins in rabbit milk. Proc. Natl Acad. Sci. USA 88, 6687–6690 (1991).
Goffin, V., Shiverick, K. T., Kelly, P. A. & Martial, J. A. Sequence-function relationships within the expanding family of prolactin, growth hormone, placental lactogen, and related proteins in mammals. Endocr. Rev. 17, 385–410 (1996).
Brooks, C. L. Molecular mechanisms of prolactin and its receptor. Endocr. Rev. 33, 504–525 (2012).
Brown, R. J. et al. Model for growth hormone receptor activation based on subunit rotation within a receptor dimer. Nat. Struct. Mol. Biol. 12, 814–821 (2005).
Qazi, A. M., Tsai-Morris, C.-H. & Dufau, M. L. Ligand-independent homo- and heterodimerization of human prolactin receptor variants: inhibitory action of the short forms by heterodimerization. Mol. Endocrinol. 20, 1912–1923 (2006).
Gadd, S. L. & Clevenger, C. V. Ligand-independent dimerization of the human prolactin receptor isoforms: functional implications. Mol. Endocrinol. 20, 2734–2746 (2006).
Brooks, A. J. & Waters, M. J. The growth hormone receptor: mechanism of activation and clinical implications. Nat. Rev. Endocrinol. 6, 515–525 (2010).
Goffin, V., Martial, J. A. & Summers, N. L. Use of a model to understand prolactin and growth hormone specificities. Protein Eng. 8, 1215–1231 (1995).
Brooks, A. J. et al. Mechanism of activation of protein kinase JAK2 by the growth hormone receptor. Science 344, 1249783 (2014).
Waters, M. J., Brooks, A. J. & Chhabra, Y. A new mechanism for growth hormone receptor activation of JAK2, and implications for related cytokine receptors. JAK-STAT 3, e29569 (2014).
Gouilleux, F., Wakao, H., Mundt, M. & Groner, B. Prolactin induces phosphorylation of Tyr694 of Stat5 (MGF), a prerequisite for DNA binding and induction of transcription. EMBO J. 13, 4361–4369 (1994).
Fresno Vara, J. A., Cáceres, M. A., Silva, A. & Martín-Pérez, J. Src family kinases are required for prolactin induction of cell proliferation. Mol. Biol. Cell 12, 2171–2183 (2001).
García-Martínez, J. M. et al. A non-catalytic function of the Src family tyrosine kinases controls prolactin-induced Jak2 signaling. Cell. Signal. 22, 415–426 (2010).
Clevenger, C. V., Furth, P. A., Hankinson, S. E. & Schuler, L. A. The role of prolactin in mammary carcinoma. Endocr. Rev. 24, 1–27 (2003).
Swaminathan, G., Varghese, B. & Fuchs, S. Y. Regulation of prolactin receptor levels and activity in breast cancer. J. Mammary Gland Biol. Neoplasia 13, 81–91 (2008).
Watkin, H. et al. Lactation failure in Src knockout mice is due to impaired secretory activation. BMC Dev. Biol. 8, 6 (2008).
Piazza, T. M., Lu, J.-C., Carver, K. C. & Schuler, L. A. SRC family kinases accelerate prolactin receptor internalization, modulating trafficking and signaling in breast cancer cells. Mol. Endocrinol. 23, 202–212 (2009).
Berlanga, J. J. et al. Prolactin activates tyrosyl phosphorylation of insulin receptor substrate 1 and phosphatidylinositol-3-OH kinase. J. Biol. Chem. 272, 2050–2052 (1997).
Miller, S. L., DeMaria, J. E., Freier, D. O., Riegel, A. M. & Clevenger, C. V. Novel association of Vav2 and Nek3 modulates signaling through the human prolactin receptor. Mol. Endocrinol. 19, 939–949 (2005).
Ali, S. et al. PTP1D is a positive regulator of the prolactin signal leading to β-casein promoter activation. EMBO J. 15, 135–142 (1996).
Brockman, J. L., Schroeder, M. D. & Schuler, L. A. PRL activates the cyclin D1 promoter via the Jak2/Stat pathway. Mol. Endocrinol. 16, 774–784 (2002).
Chan, C.-B. et al. PIKE-A is required for prolactin-mediated STAT5a activation in mammary gland development. EMBO J. 29, 956–968 (2010).
Pezet, A., Ferrag, F., Kelly, P. A. & Edery, M. Tyrosine docking sites of the rat prolactin receptor required for association and activation of stat5. J. Biol. Chem. 272, 25043–25050 (1997).
Schlessinger, J. & Lemmon, M. A. SH2 and PTB domains in tyrosine kinase signaling. Sci. STKE 2003, RE12 (2003).
Liu, B. A. et al. The human and mouse complement of SH2 domain proteins-establishing the boundaries of phosphotyrosine signaling. Mol. Cell 22, 851–868 (2006).
Bouilly, J., Sonigo, C., Auffret, J., Gibori, G. & Binart, N. Prolactin signaling mechanisms in ovary. Mol. Cell. Endocrinol. 356, 80–87 (2012).
Devi, Y. S. & Halperin, J. Reproductive actions of prolactin mediated through short and long receptor isoforms. Mol. Cell. Endocrinol. 382, 400–410 (2014).
Horseman, N. D. et al. Defective mammopoiesis, but normal hematopoiesis, in mice with a targeted disruption of the prolactin gene. EMBO J. 16, 6926–6935 (1997).
Ormandy, C. J. et al. Null mutation of the prolactin receptor gene produces multiple reproductive defects in the mouse. Genes Dev. 11, 167–178 (1997).
Wennbo, H., Kindblom, J., Isaksson, O. G. & Törnell, J. Transgenic mice overexpressing the prolactin gene develop dramatic enlargement of the prostate gland. Endocrinology 138, 4410–4415 (1997).
Hennighausen, L. & Robinson, G. W. Interpretation of cytokine signaling through the transcription factors STAT5A and STAT5B. Genes Dev. 22, 711–721 (2008).
Semprini, S. et al. Real-time visualization of human prolactin alternate promoter usage in vivo using a double-transgenic rat model. Mol. Endocrinol. 23, 529–538 (2009).
Christensen, H. R., Murawsky, M. K., Horseman, N. D., Willson, T. A. & Gregerson, K. A. Completely humanizing prolactin rescues infertility in prolactin knockout mice and leads to human prolactin expression in extrapituitary mouse tissues. Endocrinology 154, 4777–4789 (2013).
Karnik, S. K. et al. Menin controls growth of pancreatic β-cells in pregnant mice and promotes gestational diabetes mellitus. Science 318, 806–809 (2007).
Auffret, J. et al. Defective prolactin signaling impairs pancreatic β-cell development during the perinatal period. Am. J. Physiol. Endocrinol. Metab. 305, E1309–E1318 (2013).
Huang, Y. & Chang, Y. Regulation of pancreatic islet β-cell mass by growth factor and hormone signaling. Prog. Mol. Biol. Transl Sci. 121, 321–349 (2014).
Huang, C., Snider, F. & Cross, J. C. Prolactin receptor is required for normal glucose homeostasis and modulation of β-cell mass during pregnancy. Endocrinology 150, 1618–1626 (2009).
Huang, C. Wild-type offspring of heterozygous prolactin receptor-null female mice have maladaptive β-cell responses during pregnancy. J. Physiol. 591, 1325–1338 (2013).
Adán, N. et al. Prolactin promotes cartilage survival and attenuates inflammation in inflammatory arthritis. J. Clin. Invest. 123, 3902–3913 (2013).
Melmed, S. et al. Diagnosis and treatment of hyperprolactinemia: an Endocrine Society clinical practice guideline. J. Clin. Endocrinol. Metab. 96, 273–288 (2011).
Kokay, I. C., Petersen, S. L. & Grattan, D. R. Identification of prolactin-sensitive GABA and kisspeptin neurons in regions of the rat hypothalamus involved in the control of fertility. Endocrinology 152, 526–535 (2011).
Sonigo, C. et al. Hyperprolactinemia-induced ovarian acyclicity is reversed by kisspeptin administration. J. Clin. Invest. 122, 3791–3795 (2012).
Liu, X., Brown, R. S. E., Herbison, A. E. & Grattan, D. R. Lactational anovulation in mice results from a selective loss of kisspeptin input to GnRH neurons. Endocrinology 155, 193–203 (2014).
Araujo-Lopes, R. et al. Prolactin regulates kisspeptin neurons in the arcuate nucleus to suppress LH secretion in female rats. Endocrinology 155, 1010–1020 (2014).
Brown, R., Herbison, A. & Grattan, D. Prolactin regulation of kisspeptin neurons in the mouse brain and its role in the lactation-induced suppression of kisspeptin expression. J. Neuroendocrinol. 26, 898–908 (2014).
Newey, P. J. et al. Mutant prolactin receptor and familial hyperprolactinemia. N. Engl. J. Med. 369, 2012–2020 (2013).
Harris, C. Mutant prolactin receptor and familial hyperprolactinemia. N. Engl. J. Med. 370, 976 (2014).
Grossmann, M. Mutant prolactin receptor and familial hyperprolactinemia. N. Engl. J. Med. 370, 976–977 (2014).
Molitch, M. E. Mutant prolactin receptor and familial hyperprolactinemia. N. Engl. J. Med. 370, 977 (2014).
David, A. et al. Evidence for a continuum of genetic, phenotypic, and biochemical abnormalities in children with growth hormone insensitivity. Endocr. Rev. 32, 472–497 (2011).
Schlechte, J., Vangilder, J. & Sherman, B. Predictors of the outcome of transsphenoidal surgery for prolactin-secreting pituitary adenomas. J. Clin. Endocrinol. Metab. 52, 785–789 (1981).
Lecomte, P. et al. Pregnancy after intravenous pulsatile gonadotropin-releasing hormone in a hyperprolactinaemic woman resistant to treatment with dopamine agonists. Eur. J. Obstet. Gynecol. Reprod. Biol. 74, 219–221 (1997).
Ayling, R. M. et al. A dominant-negative mutation of the growth hormone receptor causes familial short stature. Nat. Genet. 16, 13–14 (1997).
Binart, N. et al. Rescue of preimplantatory egg development and embryo implantation in prolactin receptor-deficient mice after progesterone administration. Endocrinology 141, 2691–2697 (2000).
Gallego, M. I. et al. Prolactin, growth hormone, and epidermal growth factor activate Stat5 in different compartments of mammary tissue and exert different and overlapping developmental effects. Dev. Biol. 229, 163–175 (2001).
Bogorad, R. L. et al. Identification of a gain-of-function mutation of the prolactin receptor in women with benign breast tumors. Proc. Natl Acad. Sci. USA 105, 14533–14538 (2008).
NHLBI Exome Sequencing Project (ESP). Exome Variant Server [online], (2013).
Das, R. & Vonderhaar, B. K. Prolactin as a mitogen in mammary cells. J. Mammary Gland Biol. Neoplasia 2, 29–39 (1997).
Reynolds, C., Montone, K. T., Powell, C. M., Tomaszewski, J. E. & Clevenger, C. V. Expression of prolactin and its receptor in human breast carcinoma. Endocrinology 138, 5555–5560 (1997).
Wennbo, H. et al. Activation of the prolactin receptor but not the growth hormone receptor is important for induction of mammary tumors in transgenic mice. J. Clin. Invest. 100, 2744–2751 (1997).
Vomachka, A. J., Pratt, S. L., Lockefeer, J. A. & Horseman, N. D. Prolactin gene-disruption arrests mammary gland development and retards T-antigen-induced tumor growth. Oncogene 19, 1077–1084 (2000).
Oakes, S. R. et al. Loss of mammary epithelial prolactin receptor delays tumor formation by reducing cell proliferation in low-grade preinvasive lesions. Oncogene 26, 543–553 (2007).
Tworoger, S. S., Eliassen, A. H., Rosner, B., Sluss, P. & Hankinson, S. E. Plasma prolactin concentrations and risk of postmenopausal breast cancer. Cancer Res. 64, 6814–6819 (2004).
Tworoger, S. S. et al. A 20-year prospective study of plasma prolactin as a risk marker of breast cancer development. Cancer Res. 73, 4810–4819 (2013).
Tworoger, S. S., Eliassen, A. H., Sluss, P. & Hankinson, S. E. A prospective study of plasma prolactin concentrations and risk of premenopausal and postmenopausal breast cancer. J. Clin. Oncol. 25, 1482–1488 (2007).
Tikk, K. et al. Circulating prolactin and breast cancer risk among pre- and postmenopausal women in the EPIC cohort. Ann. Oncol. 25, 1422–1428 (2014).
Berinder, K., Akre, O., Granath, F. & Hulting, A.-L. Cancer risk in hyperprolactinemia patients: a population-based cohort study. Eur. J. Endocrinol. 165, 209–215 (2011).
Dekkers, O. M., Romijn, J. A., de Boer, A. & Vandenbroucke, J. P. The risk for breast cancer is not evidently increased in women with hyperprolactinemia. Pituitary 13, 195–198 (2010).
Lee, S. A. et al. A comprehensive analysis of common genetic variation in prolactin (PRL) and PRL receptor (PRLR) genes in relation to plasma prolactin levels and breast cancer risk: the multiethnic cohort. BMC Med. Genet. 8, 72 (2007).
Wagner, K.-U. & Rui, H. Jak2/Stat5 signaling in mammogenesis, breast cancer initiation and progression. J. Mammary Gland Biol. Neoplasia 13, 93–103 (2008).
Galsgaard, E. D. et al. Re-evaluation of the prolactin receptor expression in human breast cancer. J. Endocrinol. 201, 115–128 (2009).
Nitze, L. M. et al. Reevaluation of the proposed autocrine proliferative function of prolactin in breast cancer. Breast Cancer Res. Treat. 142, 31–44 (2013).
Nevalainen, M. T. et al. Prolactin and prolactin receptors are expressed and functioning in human prostate. J. Clin. Invest. 99, 618–627 (1997).
Rouet, V. et al. Local prolactin is a target to prevent expansion of basal/stem cells in prostate tumors. Proc. Natl Acad. Sci. USA 107, 15199–15204 (2010).
Li, H. et al. Activation of signal transducer and activator of transcription 5 in human prostate cancer is associated with high histological grade. Cancer Res. 64, 4774–4782 (2004).
Li, H. et al. Activation of signal transducer and activator of transcription-5 in prostate cancer predicts early recurrence. Clin. Cancer Res. 11, 5863–5868 (2005).
Gu, L. et al. Pharmacologic inhibition of Jak2-Stat5 signaling By Jak2 inhibitor AZD1480 potently suppresses growth of both primary and castrate-resistant prostate cancer. Clin. Cancer Res. 19, 5658–5674 (2013).
Goffin, V., Touraine, P., Culler, M. D. & Kelly, P. A. Drug Insight: prolactin-receptor antagonists, a novel approach to treatment of unresolved systemic and local hyperprolactinemia? Nat. Clin. Pract. Endocrinol. Metab. 2, 571–581 (2006).
Damiano, J. S. et al. Neutralization of prolactin receptor function by monoclonal antibody LFA102, a novel potential therapeutic for the treatment of breast cancer. Mol. Cancer Ther. 12, 295–305 (2013).
Damiano, J. S. & Wasserman, E. Molecular pathways: blockade of the PRLR signaling pathway as a novel antihormonal approach for the treatment of breast and prostate cancer. Clin. Cancer Res. 19, 1644–1650 (2013).
Struman, I. et al. Opposing actions of intact and N-terminal fragments of the human prolactin/growth hormone family members on angiogenesis: an efficient mechanism for the regulation of angiogenesis. Proc. Natl Acad. Sci. USA 96, 1246–1251 (1999).
Bentzien, F., Struman, I., Martini, J. F., Martial, J. & Weiner, R. Expression of the antiangiogenic factor 16K hPRL in human HCT116 colon cancer cells inhibits tumor growth in Rag1−/− mice. Cancer Res. 61, 7356–7362 (2001).
Kim, J. et al. Antitumor activity of the 16-kDa prolactin fragment in prostate cancer. Cancer Res. 63, 386–393 (2003).
Nguyen, N.-Q.-N. et al. Inhibition of tumor growth and metastasis establishment by adenovirus-mediated gene transfer delivery of the antiangiogenic factor 16K hPRL. Mol. Ther. 15, 2094–2100 (2007).
Hilfiker-Kleiner, D., Struman, I., Hoch, M., Podewski, E. & Sliwa, K. 16-kDa prolactin and bromocriptine in postpartum cardiomyopathy. Curr. Heart Fail. Rep. 9, 174–182 (2012).
D'Angelo, G. et al. 16K human prolactin inhibits vascular endothelial growth factor-induced activation of Ras in capillary endothelial cells. Mol. Endocrinol. 13, 692–704 (1999).
Tabruyn, S. P., Nguyen, N.-Q.-N., Cornet, A. M., Martial, J. A. & Struman, I. The antiangiogenic factor, 16-kDa human prolactin, induces endothelial cell cycle arrest by acting at both the G0–G1 and the G2–M phases. Mol. Endocrinol. 19, 1932–1942 (2005).
Tabruyn, S. P. et al. The antiangiogenic factor 16K human prolactin induces caspase-dependent apoptosis by a mechanism that requires activation of nuclear factor-κB. Mol. Endocrinol. 17, 1815–1823 (2003).
Lee, S.-H., Kunz, J., Lin, S.-H. & Yu-Lee, L.-Y. 16-kDa prolactin inhibits endothelial cell migration by down-regulating the Ras–Tiam1–Rac1–Pak1 signaling pathway. Cancer Res. 67, 11045–11053 (2007).
Gonzalez, C. et al. 16K-prolactin inhibits activation of endothelial nitric oxide synthase, intracellular calcium mobilization, and endothelium-dependent vasorelaxation. Endocrinology 145, 5714–5722 (2004).
Tabruyn, S. P. et al. The angiostatic 16K human prolactin overcomes endothelial cell anergy and promotes leukocyte infiltration via nuclear factor-κB activation. Mol. Endocrinol. 21, 1422–1429 (2007).
Nguyen, N.-Q.-N. et al. The antiangiogenic 16K prolactin impairs functional tumor neovascularization by inhibiting vessel maturation. PLoS ONE 6, e27318 (2011).
Bajou, K. et al. PAI-1 mediates the antiangiogenic and profibrinolytic effects of 16K prolactin. Nat. Med. 20, 741–747 (2014).
Pan, H. et al. Molecular targeting of antiangiogenic factor 16K hPRL inhibits oxygen-induced retinopathy in mice. Invest. Ophthalmol. Vis. Sci. 45, 2413–2419 (2004).
García, C. et al. Vasoinhibins prevent retinal vasopermeability associated with diabetic retinopathy in rats via protein phosphatase 2A-dependent eNOS inactivation. J. Clin. Invest. 118, 2291–2300 (2008).
Arnold, E. et al. High levels of serum prolactin protect against diabetic retinopathy by increasing ocular vasoinhibins. Diabetes 59, 3192–3197 (2010).
Triebel, J., Huefner, M. & Ramadori, G. Investigation of prolactin-related vasoinhibin in sera from patients with diabetic retinopathy. Eur. J. Endocrinol. 161, 345–353 (2009).
Hilfiker-Kleiner, D. & Sliwa, K. Pathophysiology and epidemiology of peripartum cardiomyopathy. Nat. Rev. Cardiol. 11, 364–370 (2014).
Horseman, N. D. & Gregerson, K. A. Prolactin actions. J. Mol. Endocrinol. 52, R95–R106 (2014).
Leaños-Miranda, A., Campos-Galicia, I., Ramírez-Valenzuela, K. L., Chinolla-Arellano, Z. L. & Isordia-Salas, I. Circulating angiogenic factors and urinary prolactin as predictors of adverse outcomes in women with preeclampsia. Hypertension 61, 1118–1125 (2013).
Toescu, V., Nuttall, S. L., Martin, U., Kendall, M. J. & Dunne, F. Oxidative stress and normal pregnancy. Clin. Endocrinol. (Oxf.) 57, 609–613 (2002).
Yamac, H., Bultmann, I., Sliwa, K. & Hilfiker-Kleiner, D. Prolactin: a new therapeutic target in peripartum cardiomyopathy. Heart 96, 1352–1357 (2010).
Meyer, G. P. et al. Bromocriptine treatment associated with recovery from peripartum cardiomyopathy in siblings: two case reports. J. Med. Case Rep. 4, 80 (2010).
Habedank, D. et al. Recovery from peripartum cardiomyopathy after treatment with bromocriptine. Eur. J. Heart Fail. 10, 1149–1151 (2008).
Hilfiker-Kleiner, D. et al. Recovery from postpartum cardiomyopathy in 2 patients by blocking prolactin release with bromocriptine. J. Am. Coll. Cardiol. 50, 2354–2355 (2007).
Sliwa, K. et al. Evaluation of bromocriptine in the treatment of acute severe peripartum cardiomyopathy: a proof-of-concept pilot study. Circulation 121, 1465–1473 (2010).
Sliwa, K. et al. Current state of knowledge on aetiology, diagnosis, management, and therapy of peripartum cardiomyopathy: a position statement from the Heart Failure Association of the European Society of Cardiology Working Group on peripartum cardiomyopathy. Eur. J. Heart Fail. 12, 767–778 (2010).
Halkein, J. et al. MicroRNA-146a is a therapeutic target and biomarker for peripartum cardiomyopathy. J. Clin. Invest. 123, 2143–2154 (2013).
Elms, A. F., Carlan, S. J., Rich, A. E. & Cerezo, L. Ovarian tumor-derived ectopic hyperprolactinemia. Pituitary 15, 552–555 (2012).
The authors declare no competing financial interests.
About this article
Cite this article
Bernard, V., Young, J., Chanson, P. et al. New insights in prolactin: pathological implications. Nat Rev Endocrinol 11, 265–275 (2015). https://doi.org/10.1038/nrendo.2015.36
Generation of a lentiviral vector system to efficiently express bioactive recombinant human prolactin hormones
Molecular and Cellular Endocrinology (2020)
Moringa Extract Attenuates Inflammatory Responses and Increases Gene Expression of Casein in Bovine Mammary Epithelial Cells
Asian Pacific Journal of Reproduction (2019)
Prolactin-Secreting Lung Adenocarcinoma Metastatic to the Pituitary Mimicking a Prolactinoma: A Case Report