From bench to bedside: future potential for the translation of prolactin inhibitors as breast cancer therapeutics.

A role for prolactin (PRL) in the pathogenesis of breast cancer has been confirmed at the cellular level in vitro, with multiple transgenic and knockout models in vivo, and within sizable patient populations through epidemiologic analysis. It is the obvious "next step" that these findings are translated into meaningful therapies to block PRL/PRLr function in human breast cancer. Several broad categories of PRL/PRLr antagonists are discussed in their pre-clinical context, including inhibitors of endocrine PRL elaboration, mutant ligand antagonists, ligand chimeras, and inhibitors of PRL-induced signaling and transactivation. The clinical potential for GHr antagonists are also discussed. These varied approaches all have demonstrated as proof-of-principle that PRL/PRLr antagonism can inhibit the in vitro and in vivo growth of breast cancer. Further pre-clinical development is required for most, however, before translation to clinical trials in breast cancer patients can occur.

Cyclophilin B as a co-regulator of prolactin-induced gene expression and function in breast cancer cells.

The effects of prolactin (PRL) during the pathogenesis of breast cancer are mediated in part though Stat5 activity enhanced by its interaction with its transcriptional inducer, the prolyl isomerase cyclophilin B (CypB). We have demonstrated that knockdown of CypB decreases cell growth, proliferation, and migration, and CypB expression is associated with malignant progression of breast cancer. In this study, we examined the effect of CypB knockdown on PRL signaling in breast cancer cells. CypB knockdown with two independent siRNAs was shown to impair PRL-induced reporter expression in breast cancer cell line. cDNA microarray analysis was performed on these cells to assess the effect of CypB reduction, and revealed a significant decrease in PRL-induced endogenous gene expression in two breast cancer cell lines. Parallel functional assays revealed corresponding alterations of both anchorage-independent cell growth and cell motility of breast cancer cells. Our results demonstrate that CypB expression levels significantly modulate PRL-induced function in breast cancer cells ultimately resulting in enhanced levels of PRL-responsive gene expression, cell growth, and migration. Given the increasingly appreciated role of PRL in the pathogenesis of breast cancer, the actions of CypB detailed here are of biological significance.