Xenotransplantation of surgical specimens of human breast cancer directly into genetically engineered prolactin-humanized immunodeficient mice.

Abstract

76 Background: Prolactin is an important hormone in mammary gland biology and is indispensible for lobulo-alveolar development during pregnancy and homeostasis during lactation. Prolactin has also been implicated in promoting proliferation, survival, and/ or differentiation of breast cancer. Importantly, murine and bovine prolactin, which are the major lactogens in current laboratory experimental conditions in vivo and in vitro, fail to effectively activate human prolactin receptors because of species incompatibility. Therefore, current established human breast cancer cell lines have been selected in the absence of human prolactin and do not represent the potential subgroup of cancers that depends on prolactin for survival or growth. Methods: In an effort to improve in vivo preclinical modeling of human breast cancer and to establish new human breast cancer lines that are prolactin-dependent or prolactin-sensitive, we used genetic-engineering to generate a human prolactin knock-in mouse line, which expresses physiological levels of human prolactin in place of mouse prolactin. We have crossed the prolactin-humanized mouse line into the immunodeficient NSG strain for effective xenotransplantation studies. Fresh surgical specimens from breast cancer patients were directly transplanted orthotopically into female mice within 2 hours of surgery. We then followed the growth of the xenograft tumors over time and retransplanted the tumors if they engrafted. Results: Our initial data suggested about a take rate of ~35% for the xenografted tumors. Estrogen receptor-positive luminal tumors usually have a very low engraftment rate in immunodeficient mice. However, we observed a relatively high rate of engraftment for luminal tumors. Conclusions: This new prolactin-humanized mouse model is highly relevant for in vivo exploration of tumor biology and drug response testing of breast cancer, especially for luminal subtypes.