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Molecular Mechanisms Underlying Aggressive Conversion of Dormant Breast Cancer Metastasis
Background: Metastatic recurrences frequently occur in breast cancer patients long after removal of the primary tumor. Cancer cells disseminated from the primary tumor can remain as dormant solitary cells or micrometastases until certain genetic or epigenetic events convert them into aggressive macrometastases. Despite the clinical importance, however, little is known about the molecular mechanisms for the aggressive conversion of dormant tumor cells. We had previously identified a breast cancer bone metastasis gene profile using a mouse xenograft model. Breast cancer cells lacking the expression of these genes are poorly metastatic to bone. Micrometastases generated by these cells in bone failed to grow exponentially and eventually disappeared. In rare cases, after long-term incubation, a few overt bone metastases developed. Tumor cells isolated from these lesions efficiently generated bone metastasis when they were re-injected into mice. This unique model provides us with a rare opportunity to unravel the mechanism of metastatic progression from dormancy. Objective/Hypothesis: The primary objectives of this study are to identify and validate genes that are important for metastatic progression of breast cancer cells from the dormant state and analyze the biological consequences of their expression in metastatic progression. Specific Aims: We aim to 1) discover genes that convert dormant micrometastases into overt, fast-growing macrometastasis; 2) functionally validate them using mouse models of cancer metastasis; 3) analyze the metastasis-promoting functions of these genes in breast cancer cells. Study Design: We will compare the gene expression profiles of matching pairs of highly metastatic cell lines and their dormant progenitors. Candidate genes will be overexpressed in dormant cells or repressed in metastatic cells by RNAi. In vivo metastasis assays in mice will be performed to validate their role in metastatic progression. Specific functions of these genes in metastatic processes, such as invasion, angiogenesis and osteoclast activation will be evaluated, using in vitro and in vivo assays. Potential Outcome and Benefits of the Research: These studies will identify genes that are critical for the aggressive progression of dormant breast cancer micrometastases. In addition to providing insights into the biology of breast cancer progression, results from these studies should facilitate the detection and treatment of metastatic recurrence of breast cancer.
One of the most dreadful phenomena in breast cancer is the recurrence of tumors in secondary sites many years or even decades after removal of the primary tumor. Cancer cells are often disseminated from the primary tumor early during cancer progression and remain dormant in secondary sites, such as bone, lung, or brain for a long period of time before certain changes in gene functions convert them into life-threatening, fast-growing secondary tumors (metastases) in distant target organs. Despite the clinical significance, however, very little is known about the molecular mechanisms underlying the aggressive conversion of tumor cells from dormancy. Studies in this area are often hindered by the lack of good animal models mimicking metastatic progression from dormancy. We had previously identified a gene expression profile associated with breast cancer’s ability to metastasize to bone. Human breast cancer cells that lack this profile are poorly metastatic to bone when they are inoculated into nude mice. Micrometastases generated by these cells failed to grow exponentially and eventually disappeared. In rare cases, after long term incubation, a few large bone metastases eventually developed. Tumor cells isolated from these lesions efficiently generated bone metastasis when they were re-inoculated into mice. This unique model provides us a rare opportunity to apply molecular biology approaches to unravel the mechanism for metastatic progression from dormancy. We propose to accomplish our goal by first identifying genes that are differentially expressed in the highly aggressive variants cells derived from bone lesions in mice after long term incubation of non-metastatic human breast cancer cell lines. Next, we will validate the function of these genes in mouse models for cancer metastasis. We will further investigate the biological functions that these genes contributed to promote metastatic growth. Results generated by these studies will provide insights into the genes and functions that are critical for the formation of overt metastasis from dormant tumor cells. In addition, this study will identify new markers for clinical detection of emerging metastasis in breast cancer patients and new molecular targets for development of therapeutic agents against breast cancer metastasis.