Review
Prolactin as an autocrine/paracrine growth factor in human cancer

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Abstract

Prolactin (PRL) has a dual function – as a circulating hormone and as a cytokine. This understanding is based on PRL production and distinct regulation in extrapituitary sites, its binding to membrane receptors of the cytokine receptor superfamily, and activation of signaling pathways that promote cell growth and survival. There is increasing evidence that PRL plays a role in several types of cancer in reproductive and non-reproductive tissues via local production or accumulation. The expression of both PRL and its receptor in human cancer cell lines of diverse origin lends further support to its action as an autocrine/paracrine growth factor. Establishment of PRL as an active participant in tumorigenesis should inspire the development of novel therapies aimed at reducing tumor growth by suppressing PRL production or by blocking its receptors.

Section snippets

Features of PRL as a cytokine/growth factor

PRL is a 23-kDa protein comprising 199 amino acids in four antiparallel α helices with three disulfide loops. The location of the loops is conserved but the primary sequence varies among species. Post-translational modifications, such as glycosylation, phosphorylation, cleavage and polymerization, generate molecular heterogeneity [1]. Human PRL (hPRL) is N-glycosylated on Asp31, with both glycosylated and non-glycosylated forms circulating at variable ratios. Glycosylated PRL has a lower

The PRL receptor and its signaling pathways

The PRL receptor comprises a single transmembrane region that divides the receptor into an extracellular ligand-binding domain and an intracellular domain [8]. The extracellular domain has two disulfide bonds and a Trp-Ser-X-Trp-Ser motif. The cytoplasmic domain has a proline-rich motif (‘box 1’) that couples to protein kinase signaling molecules. An intermediate receptor isoform with a deleted intracellular segment [9] in addition to two alternatively spliced short isoforms [10] have been

Dissimilar regulation of pituitary and extrapituitary PRL

Extrapituitary PRL protein is identical to pituitary PRL. In spite of the similarity of the mature proteins, PRL is differentially regulated in pituitary and extrapituitary sites [5]. As shown in Fig. 1, pituitary PRL is controlled by a proximal promoter, which requires the Pit-1 transcription factor for trans-activation. The promoter is divided into a proximal region and a distal enhancer, both of which are necessary for optimal pituitary-specific expression. The pituitary-type promoter and

Mitogenic/antiapoptotic actions of PRL

Tumors result from cellular transformation leading to an inappropriate increase in cell number. As is becoming increasingly clear, cell-cycle progression and apoptosis are intertwined. Impaired apoptosis augments tumor progression, because apoptosis eliminates cells with increased malignant potential. PRL can act as a survival (antiapoptotic) factor or as a mitogen. Indeed, PRL prolongs the lifespan of the lobuloalveoli in the lactating mammary gland, which undergo apoptosis upon cessation of

Breast cancer

PRL affects cellular growth and differentiation in the breast and is obligatory for milk production. Because the breast is the main target of PRL, it follows that PRL is also involved in its aberrant growth. This is well established in rodents, where hyperprolactinemia correlates with increased mammary tumorigenesis. PRL administration increases the incidence, size and number of spontaneous and virus-induced mammary tumors, and sustains carcinogen-induced tumor growth [23]. Moreover, transgenic

Prostatic hyperplasia and neoplasia

Prostate cancer and breast cancer have similar lifetime risks, mortality rates and dependence on hormones. Although the effects of androgens on prostate growth and tumorigenesis are undisputed, PRL is one of several cytokines with tropic effects on the prostate. In rodents, PRL participates in prostate organogenesis, secretory activity and hyperplasia [36]. PRL increases prostate weight and nuclear androgen receptor content and promotes development of dysplasia and adenocarcinoma of the

Tumors of the female reproductive tract

PRL is produced by the endometrium, myometrium and cervix. During the late luteal phase of the menstrual cycle, endometrial stromal cells differentiate under the effects of progesterone and start to express PRL [46], which is believed to play a role in trophoblast implantation and invasion [47]. Throughout pregnancy, the decidua produces large amounts of PRL, which is transported to the amniotic fluid and reaches peak levels at midgestation [48]; the function(s) of this PRL is unclear. Cultured

The hematopoietic system

The importance of PRL as an immune regulator has been questioned after finding that transgenic mice lacking either PRL or its receptor have no discernible immune deficiencies [60]. It has been proposed that PRL is either non-essential for proper immune function or plays a role only under stress. In humans, elevated serum PRL levels are occasionally seen in patients with systemic lupus erythematosus, multiple sclerosis, rheumatoid arthritis and AIDS [61], but leukemias and lymphomas are not

Summary and conclusions

PRL is an extremely versatile molecule, affecting over 100 different functions across vertebrates. These include development of the mammary gland, initiation and maintenance of lactation, immune modulation, osmoregulation and behavioral modification. At the cellular level, PRL affects mitogenic, morphogenic or secretory activities. The diversity of PRL actions is derived from several components: structural polymorphism, local production and processing, receptor isoforms and divergent

Acknowledgements

This work was supported by NIH grants ES10154, ES09555, and CA80920, NSF grant 9986713 and a grant from the Pardee Foundation.

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