The Role of Constitutively Active Prolactin Receptors in the Natural History of Breast Cancer

Abstract : Prolactin receptor (PRLR) is a single transmembrane receptor that normally requires ligand-binding to trigger intracellular signaling. Several isoforms of the human PRLR have been identified, including a long form (LF) and two short forms (SF1a and SF1b). These isoforms share identical amino acid sequence in the extracellular domain, but altered cytoplasmic domain as a consequence of alternative splicing. The extracellular domain consists of two fibronectin-like subdomains, S1 and S2. Recently we have identified the existence of naturally-occurring S2 deleted (delta S2) variants in several human cancer cell lines. We also showed that these human delta S2 isoforms were constitutively dimerized in the absence of PRL. When overexpressed in breast cancer cells, the delta S2 LF increased cell proliferation. The aim of our proposed training grant was to analyze the effect of delta S2 PRLR in a stable transfection system. We found that one of the S2 deleted short isoforms, delta S2 SF1b, was able to inhibit cell growth and migration.