Abstract A18: A novel, human-compatible mouse model for preclinical research on prolactin in breast cancer

Abstract

Abstract Over 90% of all human breast cancers express receptors for prolactin (PRL). This mitogenic hormone has been associated with an increased risk for breast cancer (as supported by epidemiological and molecular biology research). Despite this evidence, knowledge of the precise mechanisms of action for PRL in human breast cancer is limited. This is likely due to the lack of a suitable experimental model for studying the potential role of PRL in breast cancer growth and metastasis in vivo. For other reproductive hormones, the research model that has proven to be critical for preclinical studies of cancer is the grafting of human cancer cells into immunodeficient mice. Currently, no such xenograft model exists for the study of human PRL (hPRL) in breast cancer. The primary reason for this is the significant structural differences between rodent and hPRL. The mouse PRL (mPRL) hormone does not activate the hPRL receptor. Thus, grafted human cancer cells cannot respond to circulating PRL produced by the mouse host. To address this void in the repertoire of research tools, we have generated a novel set of mouse strains that have been “humanized” with regard to the structural gene, tissue expression, and secretory patterns of PRL. These mice were created using bacterial artificial chromosome technology and have been crossed onto the mouse PRL knockout background, resulting in mice that synthesize and secrete hPRL in the absence of mPRL. Our characterization studies demonstrate that the hPRL within the mice is: (1) expressed in a human-like pattern (including local production in the mammary gland), (2) secreted in a physiological fashion, and (3) controlled by known regulators (estrogen / dopamine). Further, we have shown that the hPRL produced in the mice is fully bioactive at the hPRL receptor within human breast cancer cells (T47D). We propose that these innovative models will be superior tools for examining the effects of hPRL on the growth and metastasis of human breast cancer xenografts. To this end, we have bred these mice onto the NOD/SCID immunodeficient background to allow for such preclinical studies of PRL in cancer. These novel mouse lines represent a major advancement in the research models available for the study of human breast cancer. As such, we expect that their use will have a significant impact on future diagnosis, prognosis and treatment of hormone-dependent breast cancers. Citation Format: Heather R. Christensen, Michael K. Murawsky, Karen A. Gregerson. A novel, human-compatible mouse model for preclinical research on prolactin in breast cancer. [abstract]. In: Proceedings of the AACR Special Conference: The Translational Impact of Model Organisms in Cancer; Nov 5-8, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(11 Suppl):Abstract nr A18.