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ATF-3: A Potential Target Gene for Breast Cancer Cell Growth and Metastasis
Tumor Cell Biology II
Background: TGF-beta1 (transforming growth factor-beta1), a multipotent cytokine has a wide range of physiological and pathological effects. It is the most potent known growth inhibitor for epithelial cells. In breast tissue, loss of TGF- b eta1 anti-proliferative response favors tumor formation. Moreover, in breast cancer cells, TGF- beta 1 is a crucial molecule for stimulation of invasion and formation of bone metastases. The molecular mechanisms of how TGF- b eta1 mediates these effects have yet to be completely studied. A defect in repression of transcription factors by TGF-beta1 may lead to activation of genes that participate in breast cancer progression. In our laboratory, we have found that ATF-3 (activating transcription factor-3), a member of the ATF/CREB transcription factor subfamily is strongly stimulated and its level is sustained by TGF- b eta1 in highly invasive and metastatic human and mouse mammary epithelial cancer cells. ATF-3 is also expressed in human primary breast tumors. To date, only a few target promoters for ATF-3 have been reported. We have identified for the first time that cyclin A1 (cell cycle gene), matrix metalloproteinase-13 (collagenase-3; invasive and metastasis gene), and Runx2 (a bone specific transcription factor) are ATF-3 target genes, which strongly indicate a role for ATF-3 in breast cancer growth and bone metastasis. Objective/Hypothesis: We hypothesize that inhibition of ATF-3 expression in highly invasive and metastatic breast cancer cells will reduce cell growth, invasion, and bone metastatic potential of the tumor. To test this hypothesis, we will prepare clonal human breast cancer cells with no ATF-3 expression basally or in response to TGF- beta 1 treatment by stable transfection of human breast cancer cells with either ATF-3 siRNA or inducible ATF-3 siRNA vectors. The objective of this proposal is to gain an understanding of ATF-3 function by addressing the role of ATF-3 in breast cancer cell growth and bone metastasis. Specific Aims: The proposed aims are to 1) dissect the role of ATF-3 in breast cancer cell growth, invasion, migration, apoptosis, and metastasis in vitro by utilizing cell culture model systems and 2) identify the role of ATF-3 in breast cancer bone metastasis in vivo by utilizing mouse model systems. Potential Outcomes and Benefits of the Research: To my knowledge, nothing is known about the function of ATF-3 in breast cancer cells. The studies outlined in this proposal will provide novel information about a potentially important transcription factor in breast cancer cell growth and metastasis. The investigation of the possible role of ATF-3 in metastasis of breast cancer cells to bone will give us an insight into the mechanism by which bone-specific metastasis occurs. This information will be undoubtedly used for future therapeutic targeting and for early diagnosis of aggressive primary breast tumors.
Breast cancer is a common disease that can be cured successfully by surgery or local irradiation if detected early or by preventing its spread to other organs by a process called metastasis. Thus, it is important to determine the molecular processes by which a tumor cell starts to form in breast tissue and moves from the breast to bone and other organs, causing a painful and debilitating condition. Recent results from our laboratory have revealed the presence of high levels of a protein known as ATF-3 (activating transcription factor-3) in primary human breast primary tumors and in invasive and metastatic tumor cells, suggesting that this is a common and early event in the initiation and metastasis of most of these tumors. Understanding the details of how tumors form, grow and metastasize, and how ATF-3 may be involved in these processes, is a very important issue in cancer biology that needs to be addressed in order to better treat the disease. The studies proposed here are designed to aid our understanding of how ATF-3 is involved in human breast cancer. In the proposed experiments, we will (1) dissect the role of ATF-3 in breast cancer cell growth and metastasis in a cell culture model with a recently developed powerful technique, siRNA transfection (depleting the expression of a particular gene) and (2) understand the role of ATF-3 in promoting bone specific metastasis by injecting breast cancer cells engineered to inhibit ATF-3 expression in (immunodeficient) mice and monitoring them for the efficiency of formation of bone metastases. This work will provide new insights into the development of breast tumors. This information will also be undoubtedly used for future therapeutic targeting and for early diagnosis of aggressive primary tumors.