Prolactin-Jak-Stat Signaling Pathways in Breast Cancer

Prolactin activates the Jak2-Stat5 signaling pathway, which in malignant breast epithelia may promote or suppress cellular proliferation, migration, and cellular differentiation, resulting in apparently conflicting roles for prolactin in breast cancer. The mechanisms behind the diverse effects of prolactin in breast cancer are unclear, but may be highly context-dependent. Studies investigating the interaction of PRL with other reproductive hormones, activation of alternative PRL signaling pathways such as Stat3, and genes modulated by PRL in breast cancer have been lacking. Therefore, we address three basic questions to further our understanding of the effects of PRL-Jak-Stat signaling pathways on breast cancer: 1) What is the role of PRL in the context of other reproductive hormones such as progesterone in breast cancer? 2) How do alternative signaling pathways activated by PRL such as Stat3 correlate with prognosis of breast cancer? and 3) How can identification of gene sets modulated by PRL in breast cancer shed light on the biological effects of prolactin? We report that the PRL-Stat5 pathway has the ability to suppress progesterone-induced CK5+ cancer initiating cells through its ability to inhibit progestin-driven BCL6 expression. This is consistent with a role of PRL in promoting differentiation of breast cancer cells. We also report that despite experimental evidence of Stat3 as a driver of breast cancer cell invasion and progression, nuclear localized and tyrosine-phosphorylated Stat3 (Nuc-pYStat3) had no prognostic value based on analysis of a cohort of 721 breast cancer specimens. Unexpectedly, we discovered a significant positive correlation between levels of Nuc-pYStat3 and nuclear localized and tyrosine-phosphorylated Stat5 (Nuc-pYStat5). Finally, a genome-wide transcript analysis of human breast cancer xenografts in mice treated with prolactin yielded 75 up-regulated and 55 down-regulated transcripts, and 18 breast cancer relevant transcripts were further validated. The prolactin-modulated genes identified may provide a mechanistic basis for PRL action in breast cancer and may have value as biomarkers. Collectively, we present a comprehensive analysis of PRL-Jak-Stat action in breast cancer through mechanistic, prognostic, and gene expression studies that will increase understanding of PRL action in the context of hormonal environments (progesterone), alternative signaling pathways (Stat3), and gene regulation