Altered Tumor Necrosis Factor-Alpha Signaling Pathway between High and Low Metastatic Carcinoma Clones Derived from Single Tumor

Breast cancer cells typically metastasize to the lung, liver, bones, and brain. Metastasis of the cancer cells is the primary cause of death in breast cancer patients. The mechanisms of cancer cell dissemination and proliferation at the secondary organ are not very well understood. Our goal is to identify the differences in the molecular pathway between high and low metastatic murine mammary cancer cells by using gene array. The 4T1 and 67NR cell lines are clonal populations of cells derived from a mammary carcinoma arising from a BALB/cfC3H mouse. Metastasis of disseminated 4T1 or 67NR cancer cells in BALB/c mice was investigated by systemic infusion of cancer cells by tail vein or after surgical removal of a primary tumor. To gain insight into the specific molecular pathways between these two cell lines, differences in the expression of mRNA was measured using an oligonucleotide array. Three different methods: histology, cell colony and survival assays have confirmed that 4T1 cells are highly metastatic in BALB/c mice compared to 67NR cells. The 4T1 cells developed metastases in the lungs, liver, heart, kidney, spleen, bone and brain while 67NR cells only metastasized to the lung. A gene array study confirmed that TNF-α dependent and independent apoptotic pathways are down regulated in 4T1 cells. Furthermore, a dose dependent TNF-α induced apoptotic cell death is seen in the 67NR cells. Here, we show a clear difference in tumor metastasis between the two cell lines and have shown that the TNF-α pathway could be responsible for the differences in metastatic potential.