The roles of ATF3, an adaptive-response gene, in cancer development and metastasis

Breast cancer represents a very heterogeneous class of diseases originating in the mammary epithelium which are estimated to account for 1/3 of all newly diagnosed cancers in women in the U.S. this year, equating to roughly 200,000 diagnoses. In addition to its high frequency of diagnosis among all cancers in women, breast cancer is also the second leading cause of cancer-related mortality among women. Consequently, a great deal research has been devoted to understanding the various aspects of breast cancer development and progression with the hope of identifying novel therapeutic targets in order to design treatments that possess improved clinical efficacy and patient outcomes. To this end, recent advances have shed new light on the complexity of this disease. As a result, it is now accepted that in addition to the tumorigenic changes which take place in the transformed mammary epithelial cells, the microenvironment of the newly forming tumor plays a prominent role in the progression of the disease toward invasive and metastatic phenotypes. Therefore a more complete understanding necessitates investigating how breast cancer cells and components of their microenvironment reciprocally communicate and influence each other.;The work presented in this dissertation is focused on the evaluation of the transcription factor ATF3, a molecule which functions as an integration point for cellular communication during changes in homeostasis and subsequent adaptation in response to those changes, in breast cancer development and metastasis. While the current literature supports the involvement of ATF3 in cancer biology, many of the reports are based on in vitro observations and are conflicting. To clarify some of these issues, we tested whether ATF3 plays a role in breast cancer development in vivo using a loss-of-function approach (chapter 2). The data presented demonstrate that ATF3 regulates both primary tumor growth and metastasis, and suggest that ATF3 expression in stromal cells may be contributing to this function. Following up on this observation, chapter 3 examines whether ATF3 expression in stromal cells influences breast cancer progression and metastasis. The data presented demonstrate that stromal cell expression of ATF3 does not contribute to primary tumor growth, but dramatically enhances metastasis by modulating both early (invasion/intravasation) and late (colonization) events in the metastatic process. This work was further supported by clinical findings which demonstrate that ATF3 expression in stromal cells of myeloid origin correlates with worse survival outcomes in human breast cancer patients. Moreover, this function of ATF3 was not limited to breast cancer but was also observed in melanoma where ATF3 enhanced melanoma metastasis due to its expression in stromal cells of bone marrow origin (chapter 4). Taken together, the data presented in this dissertation describe for the first time a pro-metastatic role for ATF3 in both breast cancer and melanoma due to its expression in stromal cells.