Metastasis is an extremely complex process that accounts for most cancer-related deaths. Malignant primary tumors can be removed surgically, but the cells that migrate, invade, and proliferate at distant organs are often the cells that prove most difficult to target therapeutically. There is growing evidence that host factors outside of the primary tumors are of major importance in the development of metastasis. Recently, we have shown that the bromodomain-containing protein 4 or bromodomain 4 (Brd4) functions as an inherited susceptibility gene for breast cancer progression and metastasis. In this paper, we will discuss that host genetic background on which a tumor arises can significantly alter the biology of the subsequent metastatic disease, and we will focus on the role of Brd4 in regulating metastasis susceptibility. 1. Introduction Breast cancer is the most common cancer diagnosed in women worldwide. In the United States the estimates for 2010 were 209,060 new cases of invasive breast cancer and 40,230 deaths [1]. The main cause of breast cancer-related deaths is metastatic disease. The overall 5-year relative survival of patients with metastatic breast cancer is 23%, while the relative survival of breast cancer patients with nonmetastatic tumors is 98% [2]. Patients who have no evidence of tumor dissemination at the time of diagnosis are still at risk of metastatic disease. Approximately one-third of women who are sentinel lymph node negative at the time of surgical resection of the breast primary tumor will eventually develop clinically detectable secondary tumors [3]. Therefore, understanding the mechanisms governing tumor dissemination and developing new strategies to control or effectively treat patients with or at risk of metastatic disease would significantly improve the overall outcome of the disease. Metastasis is a multistep complex process that involves the detachment of tumor cells from the primary tumor, migration and invasion through the surrounding tissues and basement membranes, intravasation and survival in the small blood vessels or lymphatic channels, and colonization in a distant target organ. These steps are usually followed by extravasation into the surrounding tissue, survival in the foreign microenvironment, proliferation, and induction of angiogenesis (Figure 1). It has become apparent that the vast majority of tumor cells within the primary tumor and also the disseminated tumor cells will not form distant metastases, either because they die or remain dormant [4]. The dormancy phenomenon probably explains what is seen in
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