Human prolactin receptors are insensitive to mouse prolactin: Implications for xenotransplant modeling of human breast cancer in mice

F. E. Utama, M. J. LeBaron, L. M. Neilson, A. S. Sultan, A. F. Parlow, K. U. Wagner, H. Rui

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Abstract

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-transferred 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.

Original languageEnglish (US)
Pages (from-to)589-601
Number of pages13
JournalJournal of Endocrinology
Volume188
Issue number3
DOIs
Publication statusPublished - Mar 1 2006

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ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

Cite this

Utama, F. E., LeBaron, M. J., Neilson, L. M., Sultan, A. S., Parlow, A. F., Wagner, K. U., & Rui, H. (2006). Human prolactin receptors are insensitive to mouse prolactin: Implications for xenotransplant modeling of human breast cancer in mice. Journal of Endocrinology, 188(3), 589-601. https://doi.org/10.1677/joe.1.06560