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Cooperation of Adipocytes with Breast Cancer Cells Promotes an Invasive Phenotype
Background: We propose the innovative hypothesis that adipocytes as stromal cells exert effects on breast tumor epithelial cells to support invasion. There is increasing epidemiological evidence between consumption of a high-fat Western diet and the incidence of breast cancer. Peroxisome proliferator-activated receptors (PPAR) are ligand-activated transcription factors expressed by adipocytes. PPAR? is expressed by adipocytes and is found in several breast tumor cell lines. Natural ligands of PPAR? (?-3 and ?-6 fatty acids, 15-deoxy?12, 14-prostaglandin J2, and some phytoestrogens) modulate adipocyte function and differentiation.
We also propose that adipocytes have the potential to modulate breast tumor cell invasion through the plasminogen activator system. PPAR? activation in adipocytes increases the expression of urokinase plasminogen activator (uPA) and the inhibitor plasminogen activator inhibitor-1 (PAI-1).
Objective/Hypothesis: We want to prove that adipocytes contribute to the invasive process in breast cancer, and that modulation of PPAR? activity in adipocytes, by diet as such, could help prevent or limit invasion. We hypothesize that PPAR? ligands upregulate PAI-1, uPA, and (urokinase plasminogen activator receptor (uPAR) in adipocytes to promote invasion-linked signaling pathways. We also hypothesize that increased expression of PAI-1 confers a survival advantage upon breast cancer cells by altering migration and invasive characteristics.
Specific Aims: 1) To treat adipocytes (wild-type and cells deficient in PAI-1, uPAR, and the clearance receptor LRP) with natural PPAR? ligands and measure PAI-1, uPA, and uPAR levels; and perform adhesion, proliferation, and migration assays; 2) To treat tumorigenic and non-tumorigenic breast cancer cell lines with natural PPAR? ligands and measure PAI-1, uPA, and uPAR levels; and perform adhesion, proliferation, migration and invasion assays; 3) To study the PPAR?-linked relationship of adipocytes and breast cancer cells in a co-cultured cell model.
Study Design: This study will use human breast cancer cell lines (MBA-MB-231 and MCF-7 cells), an immortal but non-tumorigenic human breast cell line (MCF10A), and mouse adipocytes to study the influence of PPAR? ligands.
Potential Outcome and Benefits of the Research: This proposal ascribes novel activities to tumor-associated adipocytes, to PAI-1, and to PPAR? ligands that could promote an invasive phenotype in breast cancer. In addition, our potential results have translational implications in the prevention of breast cancer through diet.
The role of dietary fats in promoting breast cancer is controversial; however, there is increasing evidence that a high-fat Western diet contributes to the occurrence of breast cancer. In the breast, several cell types, including specialized fat cells called adipocytes, surround the cells that give rise to the tumor. Adipocytes are the main lipid storage site in the breast and contribute to normal architecture and function of the breast. Adipocytes are regulated through the activation of a receptor named peroxisome proliferator-activated receptor gamma (PPAR?). Compounds within a typical Western diet, such as naturally-occurring fatting acids in many foods and the plant estrogens found in soy products, can activate PPAR?. We hypothesize that activation of PPAR? on the adipocytes alters the microenvironment surrounding the tumor cell by changing the expression of factors that promote tumor cell movement and creating a local environment that permits breast tumor cell migration and invasion.
To develop metastatic disease, the extracellular matrix or “glue” surrounding the tumor must be degraded, allowing the cancer cells to migrate into blood or lymphatic vessels and travel to sites such as the lung. Proteins called proteases mediate degradation of the extracellular matrix. Urokinase plasminogen activator (uPA) is linked to a poor prognosis for women with breast cancer. uPA/urokinase plasminogen activator receptor (uPAR)-mediated cell adhesion to the extracellular matrix protein vitronectin, can be disrupted by the addition of plasminogen activator inhibitor-1 (PAI-1). PAI-1 is also a specific inhibitor of uPA. Surprisingly, independent of uPA, an elevated level of PAI-1 is also associated with a grim prognosis for women with breast cancer.
Expression of PAI-1 and uPA has been shown to increase in non-tumor associated adipocytes in response to PPAR? activation. This association between PAI-1, uPA and PPAR? has never been studied in relation to tumor microenvironment and breast cancer. Our novel hypothesis is that activation of PPAR? by natural fatty acid components present in the Western diet will increase PAI-1, uPAR, and uPA levels. The results of this proposal will yield innovative information on how fat cells may regulate the tumor microenvironment in favor of invasion and contribute to one of the most clinically significant problems hindering the treatment of women with breast cancer, that of metastatic disease. These results also promise to provide important new information linking breast cancer prevention through proper nutrition.