The role of prolactin in mammary carcinoma

Abstract

The contribution of prolactin (PRL) to the pathogenesis and progression of human breast cancer at the cellular, transgenic, and epidemiological levels is increasingly appreciated. Acting at the endocrine and autocrine/paracrine levels, PRL functions to stimulate the growth and motility of human breast cancer cells. The actions of this ligand are mediated by at least six recognized PRL receptor isoforms found on, or secreted by, human breast epithelium. The PRL/PRL receptor complex associates with and activates several signaling networks that are shared with other members of the cytokine receptor superfamily. Coupled with the recently identified intranuclear function of PRL, these networks are integrated into the in vitro and in vivo actions induced by ligand. These findings indicate that antagonists of PRL/PRL receptor interaction or PRL receptor-associated signal transduction may be of considerable utility in the treatment of human breast cancer.

Fig. 1

PRL levels and risk of breast cancer. Relative risk (and 95% confidence intervals) of breast cancer by category of plasma PRL level, controlling and not controlling for estradiol. Data are from the only large prospective study (81) of plasma PRL and breast cancer in postmenopausal women and suggest that the observed positive association between PRL levels and breast cancer risk is independent of circulating estradiol level.

Fig. 2

Structure of the hPRLR isoforms. The two type-III fibronectin-like domains are indicated with S1 and S2 with their conserved cysteine residues and WSXWS motif marked by black or orange lines, respectively. The conserved proximal region containing the Box motifs is delineated with the corresponding tyrosine residues in each ICD. The C-terminal domains unique to the intermediate, short 1a, and short 1b hPRLR isoforms, respectively, are also noted. Affinities of receptors for ligand were calculated in all cases by radioligand binding/Scatchard analysis with the exception of the PRLBP, which was determined by biosensor analysis.

Fig. 3

Function of the PRL/PRLR complex in breast tissues. The effects of PRL on normal tissues (left panels) result in the cellular expansion of lobular units and their differentiation and outgrowth into the stroma. These effects are directly related to PRL-induced proliferation, survival, differentiation, and motility of mammary epithelium. Such actions may be due to PRL derived from both local (i.e., adjacent mammary epithelium) and distant (i.e., pituitary) sources. The functions of PRL in malignant tissues (right panels) are less clearly delineated. Although evidence exists that PRL can trigger the growth and motility of human breast cancer cells, the inability of PRL to trigger differentiation (and thereby inhibit the malignant phenotype) remains uncertain. Potential mechanisms for this include alterations in Stat5 levels or phosphorylation, quantitative changes in the expression of the various hPRLR isoforms, or alteration in the malignant epithelial cell’s responsiveness to the basement membrane, which could indirectly impact on PRLR signaling.

Fig. 4

Aspects of PRLR signaling as related to mammary gland function. Relationships between some of the salient PRLR-associated transduction cascades are demonstrated. PRL-induced receptor dimerization induces the association of the Jak2 kinase, resulting in the activation of Jak2, PRLR phosphorylation, and the association and phosphorylation of Stat5. This triggers Stat5 dimerization and nuclear translocation and events necessary for PRL-triggered mammary differentiation. Signaling through the SHC/GRB2/Ras/Raf/MEK/MAPK pathway also directly stimulates proliferation and modulates Stat activity. Furthermore, the complex between the Tec tyrosine kinase and the Vav family of guanine nucleotide exchange factors also inducibly associates with ligand-bound PRLR. This results in the exchange of GDP for GTP on the small G protein Rac, resulting in its activation and stimulation of cellular motility. Activation of Tec and the kinase Akt are directly tied to the PRL-induced activation of PI3K. The phosphatase SHP-2 also associates with the PRLR and potentiates its activity.

Fig. 5

Nuclear actions of the PRL/CypB complex. After endocytosis mediated by the PRLR, the PRL/CypB complex is retrotranslocated to the endoplasmic reticulum/Golgi, where the complex associates with the Sec61 transporter. After transport into the cytoplasm, the nuclear translocation signal sequence in the N terminus of CypB facilitates nuclear import. Within the nucleus, the PRL/CypB encounters the Stat5 dimer. Stat5, when bound to the endogenous pool of PIAS3 repressor, is unable to bind to its corresponding DNA promoter sequences. Binding of the PRL/CypB complex to the Stat5 dimer results in the release of PIAS3 (an event requiring the isomerase activity of CypB), enabling Stat5 to engage its DNA binding sequence. The binding of DNA by the Stat5 dimer results in the release of the PRL/CypB complex. Blockade of the nuclear retrotransport of PRL or inactivation of the isomerase activity of CypB significantly down-modulates PRL-driven gene expression and function.