249 : Th role of type I interferons in suppressing breast cancer metastasis to bone
2013
Breast cancer is the most common type of non-skin cancer among women. The leading cause of breast cancer mortality is not the primary tumor, but the development of metastases in distant vital organs such as lung, liver, bone and brain. Bone is the most common site of breast cancer metastasis and by the time bone metastases are detected, the disease is usually considered incurable. Our work suggests that the immune response plays an important role in blocking breast cancer spread. In particular, we have revealed that there is crosstalk between metastatic tumor cells and the host immune system via type I interferon (IFN) signaling. Analysis of bone metastases derived from mouse models and breast cancer patients revealed that tumor cell type I IFN signaling is greatly suppressed. The critical function of this pathway was confirmed as restored type I IFN signaling in cancer cells suppressed metastasis to bone in the 4T1.2 syngeneic mouse model via immune-dependent mechanisms. In addition, we have now demonstrated that the blockade of type I IFN response via use of type I IFN receptor Ifnar1 knockout mice is sufficient to accelerate or induce bone metastasis in four different murine breast cancer models, including a spontaneous murine mammary tumor model. In these studies, enhanced bone metastasis coincided with decreased immune effector natural killer (NK) cells and increased myeloid derived suppressor cells in vivo. Our work supports immune surveillance as a critical aspect of cancer metastasis and, in particular, that host type I IFN response is a key factor in suppressing bone metastasis in multiple breast cancer models. Our future focus is to dissect the role of tumor immune surveillance in dictating site-specific spread in breast cancer.
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