Research Grants Awarded
Breast Cancer and the Plasminogen Activator Inhibitor-1 Cycle
RISK and Prevention, Epidemiology
Background: We propose the innovative hypothesis that the serine protease inhibitor (serpin) plasminogen activator inhibitor-1 (PAI-1) is up-regulated as a consequence of the Metabolic Syndrome, which exerts a detrimental effect on both breast tumor epithelial cells and vascular endothelial cells to support invasion. We propose the existence of a “PAI-1 cycle”, sustained by the Metabolic Syndrome, whose action is manifest in the tumor microenvironment that promotes numerous pathological consequences. The incidence of type 2 diabetes and breast cancer is increased in the elderly, and they both share obesity as a common risk factor. We propose that adipocytokines produced due to the Metabolic Syndrome alter PAI-1 expression to promote angiogenesis, tumor-cell migration/invasion, procoagulant microparticle formation from breast tumor and endothelial cells that generate thrombin, which then further propagates PAI-1 synthesis, all of which culminates to provide a chemotherapy-resistant breast tumor microenvironment. Objective/Hypothesis: We hypothesize that adipocytokines up-regulate PAI-1 both in breast cancer cells and in endothelial cells to promote invasion-linked signaling pathways. We also hypothesize that the PAI-1 cycle in the breast tumor microenvironment leads to decreased sensitivity to chemotherapeutic agents. Specific Aims: 1) To treat both breast cancer cell lines and endothelial cells with Metabolic Syndrome adipocytokines and measure PAI-1, uPA, and uPAR levels; to perform adhesion, proliferation, migration and invasion assays (angiogenesis with endothelial cells); to characterize the procoagulant potential by formation of tumor cell microparticles; and to investigate thrombin-induced PAI-1 gene expression; 2) To test the relationship between the plasminogen activator system and Metabolic Syndrome adipocytokines in breast cancer cell lines and endothelial cells using siRNA-mediated down-regulation of PAI-1 and system components; and 3) To evaluate the relationship between the Metabolic Syndrome and plasminogen activator system components with breast cancer cells to confer a survival advantage against chemotherapeutic agents. Study Design: This study will use human breast cancer cell lines (MDA-MB-231 and MCF-7 cells), an immortal but pre-malignant human breast cell line (MCF10A), and human endothelial cells to study the influence of Metabolic Syndrome adipocytokines. Potential Outcomes and Benefit of the Research: This proposal ascribes novel activities to the Metabolic Syndrome on breast tumor cells and on tumor-associated endothelial cells, through PAI-1, that promotes an invasive phenotype in breast cancer. Our results could also answer how the PAI-1 cycle in the breast tumor microenvironment leads to decreased sensitivity to chemotherapeutic agents. Finally, our results may help explain the link between obesity, the metabolic syndrome, and breast cancer.
Background: One in nine women will be diagnosed with breast cancer. A significant percentage will already have metastatic cancers at the time of diagnosis and even though the 5-year survival rates have improved, a majority of women will still succumb to recurrent disease. An elevated level of plasminogen activator inhibitor-1 (PAI-1) is a poor prognostic factor for breast cancer patients. The role of diet in promoting breast cancer is controversial; however, there is increasing evidence that a high-fat Western diet contributes to the occurrence of breast cancer. Obesity is a worldwide problem that contributes to the risk and prognosis of many cancers, including breast cancer. Obesity and the resulting associated metabolic pathologies, termed the Metabolic Syndrome, affect >50% of adults in the U.S. Substances up-regulated from the Metabolic Syndrome, termed adipocytokines, are potent cellular regulators and may influence the metastatic potential of a tumor microenvironment. Objective/Hypothesis: Our objective is to understand why PAI-1 is detrimental to women with breast cancer. We propose a “PAI-1 cycle”, whereby expression of PAI-1 confers a survival advantage to breast cancer cells, and provides a tumor scenario more resistant to chemotherapy. We hypothesize that adipocytokines from the Metabolic Syndrome sustain the PAI-1 cycle to create a local environment that promotes breast tumor cell invasion. Specific Aims: (1) Treat both breast cancer cell lines and endothelial cells with Metabolic Syndrome adipocytokines and determine biological actions related to the PAI-1 cycle; (2) Examine both breast cancer cell lines and endothelial cells treated using small interfering RNA-mediated down-regulation of the PAI-1 system components; and (3) Study the relationship between the Metabolic Syndrome and PAI-1 cycle with breast cancer cells to confer a survival advantage against chemotherapeutic agents. Study Design: This study will use human breast cancer cell lines (MDA-MB-231 and MCF-7 cells), an immortal but pre-malignant human breast cell line (MCF10A), and human endothelial cells to study the influence of Metabolic Syndrome adipocytokines and other associated by-products. Potential Outcomes and Benefit of the Research: The association between what we call the PAI-1 cycle and Metabolic Syndrome has never been studied in relation to breast cancer. Our overall hypothesis is that the PAI-1 cycle, initiated by adipocytokines from the Metabolic Syndrome, will support breast cancer cell invasion and provide a chemo-resistant microenvironment. Our results will shed valuable information on the role of PAI-1 in one of the most significant problems hindering the treatment of women with breast cancer, invasion and metastasis. These results promise to provide important information linking breast cancer prevention through proper nutrition and exercise, and will offer new evidence between obesity, the Metabolic Syndrome, and breast cancer.