Diet-induced obesity links to ER positive breast cancer progression via LPA/PKD-1-CD36 signaling-mediated microvascular remodeling

Abstract

Obesity increases cancer risk including breast cancer (BC). However, the direct regulatory mechanisms by which obesity promotes BC progression remain largely unknown. We show that lysophosphatidic acid/protein kinase D1 (LPA/PKD-1)-CD36 signaling is a bona fide breast cancer promoter via stimulating microvascular remodeling in chronic diet-induced obesity (DIO). We observed that the growth of an estrogen receptor (ER) positive breast cancer was markedly increased when compared to the lean control, and specifically accompanied by increased microvascular remodeling in a syngeneic BC model in female DIO mice. The tumor neovessels in DIO mice demonstrated elevated levels of alpha smooth muscle actin (α-SMA), vascular endothelial growth factor receptor 2 (VEGFR 2) and endothelial differentiation gene 2/LPA receptor1 (Edg2/LPA₁), enhanced PKD-1 phosphorylation, and reduced CD36 expression. Tumor associated endothelial cells (TAECs) exposed to LPA demonstrated sustained nuclear PKD-1 phosphorylation, and elevated mRNA levels of ephrin B2, and reduced mRNA expression of CD36. TAEC proliferation also increased in response to LPA/PKD-1 signaling. These studies suggest that the LPA/PKD-1-CD36 signaling axis links DIO to malignant progression of BC via stimulation of de novo tumor arteriogenesis through arteriolar remodeling of microvasculature in the tumor microenvironment. Targeting this signaling axis could provide an additional novel therapeutic strategy.