The research focus in Dr. Clevenger’s lab is the characterization of prolactin (PRL) receptor signal transduction and function as it pertains to breast cancer and mammary gland development. The PRL receptor (PRLr) is a member of the growth factor/cytokine receptor family, which includes the receptors for interleukin 2-7, GM-CSF, erythropoietin, and growth hormone. Within humans, PRL functions at the endocrine and autocrine/paracrine levels as a growth and differentiation factor within the breast, a hypothesis first postulated by our laboratory. Indeed, recent data we have also demonstrated that PRL serves as a chemoattractant for human breast carcinoma. Therefore, one of our major aims is the characterization of those mechanisms that regulate PRL/PRLr expression and action in both normal and neoplastic tissues. PRL action in human tissues is mediated by six prolactin receptor isoforms, three of which were initially identified and characterized by our lab. The molecular dissection of PRL receptor isoform structure/function, therefore, is another research focus. These studies utilize both biochemical and biophysical approaches to examine PRL-PRLr binding and the interaction of the PRLr with its associated transduction pathways that include JAK/Stat, Vav2/Rac, Fyn, Tec, and Bcl-2/Bag-1. In addition to these non-genomic transduction pathways, we have recently identified a direct genomic action of PRL on gene expression. This action is mediated by the chaperone cyclophilin B (CypB), which retrotransports endocytosed ligand into the nucleus, where the PRL/CypB complex directly interacts with and activates the Stat5 transcription factor. The PRL/CypB complex serves to activate Stat5 by blocking the association of the SUMO E3 ligase PIAS3 and its attendant sumolyation of Stat5; furthermore, the association with the Cyp-regulated proto-oncogene c-myb is stimulated. As such our findings present vantage points in the development of novel therapies aimed at modulating PRL action during the differentiation of the human breast and the pathogenesis of malignancy in this tissue.
Publications:
Miller SL, DeMaria JE, Fikaris AJ, Freier DO, Riegel AM, Clevenger CV: Novel association of Vav2 and Nek3 modulates signaling through the human prolactin receptor. Molecular Endocrinology, 19:939-949, 2005.
Clevenger CV, Furth PA, Hankinson SE, Schuler LA: The role of prolactin in mammary carcinoma. Endocrine Reviews, 24:1-27, 2003.
Kline JB, Rycyzyn MA, Clevenger CV: Characterization of a novel and functional human prolactin receptor isoform (DS1PRLr) containing only one extracellular fibronectin-like domain. Molecular Endocrinology, 16:2310-2322, 2002.
Rycyzyn MA and Clevenger CV: The intranuclear prolactin/cyclophilin B complex as a transcriptional inducer. Proc Natl Acad Sci, USA, 99:6790-6795, 2002.
Kline JB and Clevenger CV: Identification and characterization of the prolactin binding protein (PRLBP) in human serum and milk. J Biol Chem, 276: 24760-24766, 2001.
Kline JB, Moore D, Clevenger CV: Activation and association of the Tec tyrosine kinase with the prolactin receptor: Mapping of a Tec/Vav – receptor binding site. Molecular Endocrinology, 15:832-841, 2001.
Rycyzyn MA, Reilly SC, O’Malley K, Clevenger CV: Role of cyclophilin B in prolactin transduction and nuclear retrotranslocation. Molecular Endocrinology, 14: 1175-1186, 2000.
Maus MV, Reilly SC, Clevenger CV: Prolactin as a chemoattractant for human breast cancer. Endocrinology, 140: 5447-5450, 1999.
Kline JB, Roehrs H, Clevenger CV: Functional characterization of the intermediate isoform of the human prolactin receptor. J Biol Chem, 274:35461-35468, 1999.
