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Hypoxic Response And Inflammation: Role In Breast Cancer Progression.
Investigator Initiated Research
Breast cancer is marked both by infiltration by inflammatory cells and by inflammation itself. There are also strong associations between micro-environmental hypoxia and breast cancer progression and metastasis, and many studies have established that hypoxia is a negative prognostic marker in human breast cancer. For example, expression of the hypoxia-induced transcription factor HIF-1 has been shown to be one of the most accurate markers found for poor prognosis in human breast cancer. We were the first group to demonstrate the requirement for HIF-1 in inflammation, and have since shown that the HIF-1 response is a key trigger for many aspects of inflammatory response. We have also shown that loss of HIF in the transformed epithelium in a mouse model of breast cancer reduces both tumor progression and metastasis. The work proposed here will address a key question in trying to understand breast cancer progression, inflammation, and hypoxia: what is the role of HIF in tumor-associated macrophages during breast cancer progression? Hypoxia is a key characteristic of that tumor microenvironment, and as mentioned above correlated with poor prognosis and metastatic progression in human breast cancer. This proposal for the Komen Foundation focuses on the relationship between the macrophage, hypoxia, and breast cancer progression. The proposed experiments are on mice with tissue-specific deletions of the HIF transcription factor (HIF-1a) in a breast cancer model. We have found exciting evidence that HIF expression and hypoxia in tumor-associated macrophages act in tumor expansion; and we have uncovered early proof that when this response is blocked, tumor growth is dramatically slowed and tumor progression retarded. The experiments proposed focus on understanding how hypoxia influences tumor-associated macrophages in promoting breast cancer progression, with the aim of evaluating both inflammatory activation and HIF function as targets for therapy in breast cancer. The work has three experimental aims: The first experimental aim will explore the relationship between hypoxic response in tumor associated macrophages in a breast cancer model and the induction of angiogenesis. A number of angiogenic factors and response pathways are controlled by HIF transcriptional activation. These include the vascular endothelial growth factor (VEGF) gene and one of its receptors, VEGFR1. We will use mice with targeted inactivation of HIF-1a in macrophages to determine the role of hypoxic response and inflammation in inducing neo-vascularization of mammary cancers during tumorigenic progression. This will allow us to determine the overall level of macrophage participation in the angiogenesis of mammary tumors, and also its relationship to intratumoral hypoxia. The second experimental aim will ask how tumorigenic progression is influenced by the hypoxia response pathway by comparing progression of pre-malignant stages to malignancy and tumor growth during progression, with the growth of fully transformed, malignant epithelium transplanted into macrophage knockout animal mammary fat pads. These experiments will allow us to determine the relationships between inflammation, hypoxia, and progression versus effects on simple growth of malignant cells/tissues in the absence of further transformation. These experiments will additionally be complemented by analysis of progression in breast cancer models where both the tumor-associated macrophages and the epithelial cells have been targeted for deletion of HIF pathway components; these latter experiments will address potential synergies in targeting the HIF pathway in breast cancer. Finally, we will determine the effect of loss of hypoxic response in inflammation on metastasis of mammary carcinomas. We have recently shown that loss of HIF response in mammary epithelium strongly suppresses metastatic tumor seeding and growth. For this third aim we will determine the role played by hypoxic response in inflammatory cells on the rates of metastatic growth; we will follow this with experiments to delineate the mechanistic relationships between hypoxia and induction of HIF target genes, and the processes which foster tumor metastasis in breast cancer.
Inflammation is a key factor in the growth of breast cancers; this is shown by the reduced rates of breast cancer seen in women who take anti-inflammatory drugs, and by the high numbers of inflammatory cells found in most breast tumors. Low oxygen levels, or hypoxia, are also found in many if not most breast cancers, and significant amounts of low levels of oxygen within tumors are correlated with poor outcome in breast cancer. One factor, termed the hypoxia-inducible factor, or HIF, is found in both human breast cancer and in inflammatory cells, and has been shown to be correlated with poor prognosis; indeed, one worker in the field has claimed that HIF-1a is one of the most accurate markers for poor outcome in breast cancer found to date.
We have shown that loss of HIF-1a blocks inflammation in experimental animals. We have also shown that removing HIF-1a from breast cancer cells in mice slows both tumor growth and blocks breast cancer metastasis to the lungs. Since this one factor can coordinate both cancer cells and inflammatory cells, we propose here to try to understand how this factor works in inflammatory cells in a mouse model of breast cancer. To do this, we have removed the factor specifically from cells that cause inflammation, and in our preliminary data we show that this reduces mammary tumor growth. The proposal details experiments to understand why this reduction in mammary tumor growth occurs, with a focus on the processes of new blood vessel growth in the tumor, and tumor metastasis; we believe that both of these are strongly impacted by inflammation and hypoxia. The HIF pathway and a number of the genes that it controls, such as the angiogenic factor VEGF, as well as many inflammatory pathways, are currently the subject of a great deal of drug development activity by pharmaceutical companies. This work will provide the basic, pre-clinical data to establish whether breast cancer will be a good setting for testing those drugs for anti-cancer activity. Our data indicates that there is a strong likelihood that targeting the HIF pathway and inflammation could be a very important new avenue for breast cancer treatment.