Human prolactin receptors are insensitive to mouse prolactin: implications for xenotransplant modeling of human breast cancer in mice. J Endocrinol 2006 Mar;188(3):589-601
Date
03/09/2006Pubmed ID
16522738DOI
10.1677/joe.1.06560Scopus ID
2-s2.0-33645213701 (requires institutional sign-in at Scopus site) 54 CitationsAbstract
Experimental testing of growth, metastatic progression and drug responsiveness of human breast cancer in vivo is performed in immunodeficient mice. Drug candidates need to show promise against human breast cancer in mice before being allowed into clinical trials. Breast cancer growth is under endocrine control by ovarian steroids and the pituitary peptide hormone prolactin. While it is recognized that the most relevant biologic effects of prolactin are achieved with prolactin from the matching species, the biologic efficacy of mouse prolactin for human prolactin receptors has not been recorded. Thus, it is unclear whether the mouse endocrine environment adequately reflects the hormonal environment in breast cancer patients with regard to prolactin. We now show both recombinant and natural pituitary-derived mouse prolactin to be a poor agonist for human prolactin receptors. Mouse prolactin failed to induce human prolactin receptor-mediated biologic responses of cell clustering, proliferation, gene induction and signal transduction, including activation of Stat5, Stat3, Erk1/2 and Akt pathways. Consistent data were derived from human breast cancer lines T-47D, MCF-7 and ZR-75.1, as well as human prolactin receptor-transfected COS-7 and 32D cells. Failure of mouse prolactin to activate human prolactin receptors uncovers a key deficiency of the mouse endocrine environment for human xenotransplant studies. Since most human breast cancers express prolactin receptors, human breast cancer transferred into mice is unnaturally selected for growth in the absence of circulating prolactin. The new insight raises concerns about the validity of analyzing biology and drug responsiveness of human breast cancer in existing mouse xenotransplant models.
Author List
Utama FE, LeBaron MJ, Neilson LM, Sultan AS, Parlow AF, Wagner KU, Rui HMESH terms used to index this publication - Major topics in bold
Analysis of VarianceAnimals
Breast Neoplasms
Cell Line, Tumor
Cell Proliferation
Electroporation
Female
Humans
Immunoblotting
Immunoprecipitation
Mice
Mice, Nude
Models, Animal
Neoplasm Transplantation
Prolactin
Protein Binding
Receptors, Prolactin
Reverse Transcriptase Polymerase Chain Reaction
STAT5 Transcription Factor
Species Specificity
Transplantation, Heterologous
