Abstract S1-8: Prolactin-humanized mice: an improved animal recipient for therapy response-testing of patient-derived breast cancer xenotransplants

Abstract

Abstract Eighty percent of newly diagnosed breast cancer represents estrogen receptor(ER)-positive luminal subtypes. Many patients with luminal breast cancer develop antiestrogen resistant disease. It has historically been particularly difficult to establish ER-positive breast cancer lines from primary breast cancer in the laboratory or in mice. Murine and bovine prolactins, the major lactogens in current laboratory experimental in vivo and in vitro conditions, fail to activate human prolactin receptors because of species incompatibility. In fact, murine prolactin is a potent antagonist for human prolactin receptors. Because ER-positive, luminal breast cancers also express prolactin receptors, we hypothesized that lack of human lactogenic activity under experimental conditions selected against establishment of ER-positive breast cancer in the laboratory. We therefore genetically engineered mice to express physiological levels of human prolactin in place of mouse prolactin and backcrossed the mice for ten generations into the immunodeficient NSG strain. The resulting hPRL.NSG mice have a greatly improved take rate for ER positive, luminal type of breast cancer, suggesting key tumor-promoting roles for prolactin in luminal breast cancer. A panel of novel transplantable human breast cancer lines has been established in hPrl.NSG mice, the majority of which are ER-positive. The transplantable lines maintain key histopathological characteristics and expression of major marker proteins of the primary patient tumors. Intriguingly, initial tumor establishment and growth rates of breast cancer xenografts were consistently greater in the hPrl.NSG mice than in wildtype NSG mice. Furthermore, tumors grown in hPrl.NSG were more responsive to tamoxifen than size-matched tumors grown in wildtype NSG mice. At least two new tumor lines examined so far develop spontaneous distant metastases in hPrl.NSG mice, with evidence of prolactin-dependent progression of ER-positive disease. Collectively, these observations validate the hPrl.NSG mice as an improved recipient for preclinical modeling of human breast cancer in vivo, both for therapeutic targeting of prolactin-pathways and other growth and survival pathways, as well as overcoming anti-estrogen resistance. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr S1-8.