title: Anti-metastatic outcome of isoform-specific prolactin receptor targeting in breast cancer.
abstract: Controversy exists concerning the role of the long prolactin receptor (PRLR) in the progression of breast cancer. By targeting pre-mRNA splicing, we succeeded in knocking down only the long PRLR in vivo, leaving the short forms unaffected. Using two orthotopic and highly-metastatic models of breast cancer, one of which was syngeneic (mouse 4T1) to allow assessment of tumor-immune interactions and one of which was endocrinologically humanized (human BT-474) to activate human PRLRs, we examined the effect of long PRLR knockdown on disease progression. In both models, knockdown dramatically inhibited metastatic spread to the lungs and liver and resulted in increased central death in the primary tumor. In the syngeneic model, immune infiltrates in metastatic sites were changed from innate inflammatory cells to lymphocytes, with an increase in the incidence of tumor-specific cytotoxic T cells. Long PRLR knockdown in three-dimensional culture induced apoptosis of tumor-initiating/cancer stem cells (death of 95% of cells displaying stem cell markers in 15 days). We conclude that the long PRLR plays an important role in breast cancer metastasis.
authors.affiliation: Division of Biomedical Sciences, School of Medicine, University of California, Riverside, CA 92521, USA; Laboratory for Veterinary Physiology, Kitasato University, Towada, Aomori, 03486-28, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Yonezawa
authors.affiliation: Division of Biomedical Sciences, School of Medicine, University of California, Riverside, CA 92521, USA.
authors.forename: Kuan-Hui Ethan
authors.initials: KH
authors.lastname: Chen
authors.affiliation: Division of Biomedical Sciences, School of Medicine, University of California, Riverside, CA 92521, USA.
authors.forename: Mrinal K
authors.initials: MK
authors.lastname: Ghosh
authors.affiliation: Division of Biomedical Sciences, School of Medicine, University of California, Riverside, CA 92521, USA.
authors.forename: Lorena
authors.initials: L
authors.lastname: Rivera
authors.affiliation: Division of Biomedical Sciences, School of Medicine, University of California, Riverside, CA 92521, USA.
authors.forename: Riva
authors.initials: R
authors.lastname: Dill
authors.affiliation: Division of Biomedical Sciences, School of Medicine, University of California, Riverside, CA 92521, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Ma
authors.affiliation: Division of Biomedical Sciences, School of Medicine, University of California, Riverside, CA 92521, USA.
authors.forename: Pedro A
authors.initials: PA
authors.lastname: Villa
authors.affiliation: Laboratory for Veterinary Physiology, Kitasato University, Towada, Aomori, 03486-28, Japan.
authors.forename: Mitsumori
authors.initials: M
authors.lastname: Kawaminami
authors.affiliation: Division of Biomedical Sciences, School of Medicine, University of California, Riverside, CA 92521, USA. Electronic address: Ameae.walker@ucr.edu.
authors.forename: Ameae M
authors.initials: AM
authors.lastname: Walker
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000556:secondary; D008175:Lung Neoplasms / Q000556:secondary; D051379:Mice; D008807:Mice, Inbred BALB C; D009362:Neoplasm Metastasis / Q000517:prevention & control; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000502:physiology; D011981:Receptors, Prolactin / Q000037:antagonists & inhibitors / Q000502:physiology*
chemical_list: D020033:Protein Isoforms; D011981:Receptors, Prolactin
keywords: Cancer stem cells; Metastasis; Prolactin receptor; Splice isoform