Trends in Endocrinology & Metabolism
ReviewProlactin as an autocrine/paracrine growth factor in human cancer
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.
References (71)
Functional characterization of the intermediate isoform of the human prolactin receptor
J. Biol. Chem.
(1999)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.
(2001)A serum prolactin-binding protein: implications for growth hormone
Trends Endocrinol. Metab.
(2001)- et al.
Prolactin receptor antagonists that inhibit the growth of breast cancer cell lines
J. Biol. Chem.
(1995) Prolactin: the forgotten hormone of human breast cancer
Pharmacol. Ther.
(1998)CCAAT/enhancer-binding proteins are mediators in the protein kinase A-dependent activation of the decidual prolactin promoter
J. Biol. Chem.
(1999)Stat5a and Stat5b: fraternal twins of signal transduction and transcriptional activation
Cytokine Growth Factor Rev.
(1999)Constitutive tyrosine phosphorylation of ErbB-2 via Jak2 by autocrine secretion of prolactin in human breast cancer
J. Biol. Chem.
(2000)Prolactin-dependent upregulation of BRCA1 expression in human breast cancer cell lines
Biochem. Biophys. Res. Commun.
(1999)Prolactin receptor expression in the developing human prostate and in hyperplastic, dysplastic, and neoplastic lesions
Am. J. Pathol.
(1999)