Abstract 434: Human breast cancer cells are reprogrammed to a non-tumorigenic/non-metastatic cell fate in vivo

Abstract

Abstract Breast cancer is the second leading cause of cancer deaths in the United States. At the present, the etiology of breast cancer is unknown; however the possibility of a distinct cell of origin, i.e. a cancer stem cell, is a heavily investigated area of research. Influencing signals from the tissue niche are known to affect stem cells. Literature has shown that cancer cells lose their tumorigenic potential and display ‘normal’ behavior when placed into ‘normal’ ontogenic environments. Therefore, it may be the case that the tissue microenvironment is able to generate signals to redirect cancer cell fate. Here, we show that that human metastatic, non-metastatic, and metastasis-suppressed breast cancer cells proliferate and contribute to normal mammary gland development in-vivo without tumor formation. Human metastatic (MDA-MB-231-GFP), non-metastatic (MDA-MB-468-GFP), and metastatsis-suppressed (MDA-MB-231BRMS-GFP) breast cancer cells were mixed with mouse mammary epithelial cells at ratios of 1:5 (MDA-231-GFP) or 1:50 (MDA-468-GFP, MDA-231BRMS-GFP) in phosphate-buffered saline. Ten microliters of the solution was injected into mammary fat pads cleared of host epithelium of 3-week-old female athymic nude mice. Immortalized human mammary epithelial cells (hTERT-HME1; 50K) and mouse mammary epithelial cells (50K) were independently inoculated into epithelium-free fat pads as controls. Ten to twelve weeks later, mice were euthanized and their fat pad outgrowths harvested for histological examination and immunostaining for mammary epithelial cell markers, keratin 14 and casein (human vs. mouse). Tissue fragments excised from first-generation fat pad outgrowths were implanted into the cleared mammary fat pads of a new group of 3-week-old female athymic nude mice to produce second-generation outgrowths. When MDA-MB-231-GFP metastatic, MDA-MB-231BRMS1-GFP metastasis-suppressed, and MDA-MB-468-GFP non-metastatic breast cancer cells were mixed with mouse mammary epithelial cells and inoculated into mammary fat pads of mice cleared of epithelium, no primary tumors or bone metastases were formed, and the human breast cancer cells 1) contributed to the formation of the regenerated mouse mammary gland and 2) expressed the human mammary epithelial marker keratin 14 in consecutive sections of first generation transplants. Furthermore, mouse mammary epithelial cells expressing mouse keratin 14 were found juxtaposed to human cancer cells expressing human keratin 14. Overall, these data suggest that human metastatic, non-metastatic, and metastasis-suppressed breast cancer cells can be redirected towards a non-tumorigenic/non-metastatic phenotype by signals produced by the regenerating mouse mammary gland. Supported by the National Institutes of Health, National Cancer Institute Intramural Program. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 434. doi:10.1158/1538-7445.AM2011-434