Acetylation Modulates Prolactin Receptor Dimerization in Breast Cancer

Prolactin (PRL) and PRL receptor (PRLR) are essential in mammary gland development during pregnancy and lactation. Overexpression of PRLR has been widely detected in breast cancers. Here we found that in T47D and MCF7 cells, PRL treatment induces CREB‐binding protein (CBP) nuclear exportation and CBP‐PRLR association. Mass spectrometry analysis showed that PRLR associated CBP acetylates PRLR on multiple lysine sites along the C‐loop. FRET gave the evidence that PRLR also undergoes C‐loop dimerization which is tightly regulated by acetylation. PRLR C‐loop undergoes acetylation‐dependent dimerization for SIRT specific inhibitor nicotinamide treatment enhanced PRLR full length and PRLR C‐loop protein‐protein interaction. Such C‐loop dimerization relies on the interaction in multiple regions from the membrane‐proximal region to the membrane‐distal region, because the C‐loop dimerization is disrupted only when all acetylated lysines (K) are substituted with arginines (R). C‐loop associated STAT5 is only activated by the dimerized PRLR, suggesting a receptor transactivation mechanism. PRLR activated STAT5 is also acetylated by CBP and undergoes acetylation‐dependent dimerization and gene regulation. Overexpression of SIRT2 or HDAC6 blocks PRLR and STAT5 activation. Our results indicate that reversible acetylation provides the rheostat‐like regulation for the PRLR‐STAT5 route for activation.