Abstract
Background: Obesity increases breast cancer (BC) risk. However, the molecular links by which obesity promotes BC progression remain largely unknown. Lysophosphatidic acid (LPA) produced excessively in obesity is a lipid signaling mediator essential for vascular remodeling, angiogenesis and BC progression, in which protein kinase D1 (PKD-1) and angiogenic regulator CD36 play an important role. Hypothesis: Obesity promotes microvascular remodeling and angiogenesis for BC progression via LPA/PKD-1-CD36 signaling axis. Methods: The hypothesis was tested in tumor-associated endothelial cells (TAECs), BC cells and a diet-induced obesity (DIO) mouse model. Lentiviral transduction, qPCR, Western blotting and Halo pull-down assays, angiogenesis profiling and immunofluorescence and immunohistochemical assays were applied for analysis of gene and protein expression, and relevant signaling pathways. Seahorse Bioscience Extracellular Flux Analyzer was used to detect cellular mitochondrial respiration. Results: LPA/PKD-1-CD36 signaling was a bona fide BC promoter via stimulating microvascular remodeling in chronic DIO. ER + breast cancer grew faster and larger in the DIO mice than in the lean control, specifically accompanied by enhanced microvascular remodeling in a syngeneic ER + BC model. The expression of vascular endothelial cell growth receptor 2, and endothelial differentiation gene 2/LPA receptor 1 (Edg2/LPA 1 ), and phospho-PKD-1 also increased, accompanied by CD36 downregulation in the tumor endothelium. TAECs exposed to LPA showed sustained nuclear PKD-1 phosphorylation, and elevated mRNA levels of ephrin B2, and reduced CD36 mRNA expression, along with increased proliferation, which was inhibited by a selective PKD inhibitor. Finally, LPA/PKD-1 signaling changed mitochondrial respiration in ECs and breast adenocarcinoma cells. Conclusion: These studies suggest that LPA/PKD-1-CD36 signaling axis links DIO to BC progression via stimulation of arteriolar remodeling of microvasculature in the tumor microenvironment. The axis-mediated changes in cellular metabolism may promote the microvascular remodeling process. Targeting this signaling axis could provide an additional novel therapeutic strategy against breast cancer.
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