Breast Cancer and Prolactin - New Mechanisms and Models

Abstract

The pathogenesis of breast cancer is driven by multiple hormones and growth factors. One of these, prolactin (PRL), contributes to both mammary differentiation and oncogenesis, and yet the basis for these disparate effects has remained unclear. The focus of this review is to examine and place into context 2 recent studies that have provided insight into the roles of PRL receptors and PRL in tumorigenesis and tumor progression. One study provides novel evidence for opposing actions of PRL in the breast being mediated in part by differential PRL receptor (PRLr) isoform utilization. Briefly, homomeric complexes of the long isoform of the PRLr (PRLrL-PRLrL) promotes mammary differentiation, while heteromeric complexes of the intermediate and long PRLr (PRLrI-PRLrL) isoforms trigger mammary oncogenesis. Another study describes an immunodeficient, prolactin-humanized mouse model, NSG-Pro, that facilitates growth of PRL receptor-expressing patient-derived breast cancer xenografts. Evidence obtained with this model supports the interactions of physiological levels of PRL with estrogen and ERBB2 gene networks, the modulatory effects of PRL on drug responsiveness, and the pro-metastatic effects of PRL on breast cancer. This recent progress provides novel concepts, mechanisms and experimental models expected to renew interest in harnessing/exploiting PRLr signaling for therapeutic effects in breast cancer.

Keywords: Jak2/Stat5; endocrine resistance; metastasis; mouse models.

Figure 1.

Working model of PRLrI-driven breast cancer, PRLrI expression in human breast cancer, and the PRLrI is co-transforming with the PRLrL. A, PRLrI is generated by an out-of-frame alternative splicing event, losing both the phospho-degron serine 349 (S349) as well as both putative Stat5A docking sites, tyrosines 509 and 611 (Y509 and Y611, respectively), while gaining a novel 13–amino acid tail (I-Tail). B, Altered stability and/or signaling of the PRLrL + I heterodimer, distinct from that of either homodimer, contributes to mammary transformation.

Figure 2.

Working model of the relative impact of predominant PRLrL-PRLrL homodimers vs increased proportion of PRLrL-PRLrI heterodimers on breast cancer biology and tumor phenotype.