Inhibition of the Activity of Cyclophilin A Impedes Prolactin Receptor-Mediated Signaling, Mammary Tumorigenesis, and Metastases

• DOI: 10.1016/j.isci.2020.101581
• Publication Date: 2020-09-19T06:53:46Z
• Authors: Shawn Hakim; Justin M. Craig; Jennifer E. Kobli...; Charles V. Clevenger
• Keywords: Cypa; Prolyl isomerase

Prolactin (PRL) and its receptor (PRLr) play important roles in the pathogenesis of breast cancer. Cyclophilin A (CypA) is a cis-trans peptidyl-prolyl isomerase (PPI) that constitutively associated with PRLr facilitates activation tyrosine kinase Jak2. Treatment non-immunosuppressive prolyl inhibitor NIM811 or CypA short hairpin RNA inhibited PRL-stimulated signaling, cancer cell growth, migration. Transcriptomic analysis revealed two-thirds top 50 PRL-induced genes reduction gene pathways signaling. In vivo treatment TNBC xenograft lessened primary tumor growth induced central necrosis. Deletion MMTV-PyMT mouse model demonstrated inhibition tumorigenesis significant lung lymph node metastasis. The regulation PRLr/Jak2-mediated biology by demonstrates can function as potential therapeutic.