Abstract
Breast cancer is the most common cancer in women, and this prevalence has a major impact on health worldwide. Localized breast cancer has an excellent prognosis, with a 5-year relative survival rate of 85%. However, the survival rate drops to only 23% for women with distant metastases. To date, the study of breast cancer metastasis has been hampered by a lack of reliable metastatic models. Here we describe a novel in vivo model using human breast cancer xenografts in NOD scid gamma (NSG) mice; in this model human breast cancer cells reliably metastasize to distant organs from primary tumors grown within the mammary fat pad. This model enables the study of the entire metastatic process from the proper anatomical site, providing an important new approach to examine the mechanisms underlying breast cancer metastasis. We used this model to identify gene expression changes that occur at metastatic sites relative to the primary mammary fat pad tumor. By comparing multiple metastatic sites and independent cell lines, we have identified several gene expression changes that may be important for tumor growth at distant sites.
Highlights
Metastatic disease is responsible for greater than 80% of all deaths from carcinoma [1]
NOD scid gamma (NSG) mice are highly susceptible to metastasis formation In order to develop a system that models the entire metastatic process, we injected aggressive basal MDA-MB-231 human breast carcinoma cells orthotopically into the mammary fat pads of nine severely immunocompromised NSG mice
Organs were harvested and the presence of metastases was confirmed by H&E and cytokeratin 18 (CK18) staining of tissue sections (Figure 1D)
Summary
Metastatic disease is responsible for greater than 80% of all deaths from carcinoma [1]. The most commonly used model of breast cancer metastasis relies on injecting tumor cells directly into the circulation via the tail vein or left ventricle of the heart [5,6] This model removes the requirement for cells to invade and intravasate, and cannot be used to study the complete metastatic process. Using orthotopic injection of human breast cancer cells into the mammary fat pads of NOD scid gamma (NSG) mice [7], metastases in distant organs consistently develop without the need for resection of the primary tumor. This model can be used to study the metastatic process in its entirety. These gene expression changes may regulate metastatic growth at distant sites and may represent potential therapeutic targets to inhibit metastatic disease
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