title: 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.
authors.affiliation: Blood Research Institute, Blood Center of Wisconsin, Milwaukee, Wisconsin, USA.
authors.forename: Liuyi
authors.initials: L
authors.lastname: Dong
authors.affiliation: Blood Research Institute, Blood Center of Wisconsin, Milwaukee, Wisconsin, USA.|Edison Biotechnology Institute and Department of Chemistry and Biochemistry, Ohio University, Athens, Ohio, USA.
authors.forename: Ye
authors.initials: Y
authors.lastname: Yuan
authors.affiliation: Blood Research Institute, Blood Center of Wisconsin, Milwaukee, Wisconsin, USA.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Opansky
authors.affiliation: Blood Research Institute, Blood Center of Wisconsin, Milwaukee, Wisconsin, USA.
authors.forename: Yiliang
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Pathology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
authors.forename: Irene
authors.initials: I
authors.lastname: Aguilera-Barrantes
authors.affiliation: Edison Biotechnology Institute and Department of Chemistry and Biochemistry, Ohio University, Athens, Ohio, USA.
authors.forename: Shiyong
authors.initials: S
authors.lastname: Wu
authors.affiliation: Blood Research Institute, Blood Center of Wisconsin, Milwaukee, Wisconsin, USA.
authors.forename: Rong
authors.initials: R
authors.lastname: Yuan
authors.affiliation: Diagnostic Radiology and Nuclear Medicine, University of Maryland Medical Center, Baltimore, Maryland, USA.
authors.forename: Qi
authors.initials: Q
authors.lastname: Cao
authors.affiliation: Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
authors.forename: Yee Chung
authors.initials: YC
authors.lastname: Cheng
authors.affiliation: Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
authors.forename: Daisy
authors.initials: D
authors.lastname: Sahoo
authors.affiliation: Blood Research Institute, Blood Center of Wisconsin, Milwaukee, Wisconsin, USA.|Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
authors.forename: Roy L
authors.initials: RL
authors.lastname: Silverstein
authors.affiliation: Blood Research Institute, Blood Center of Wisconsin, Milwaukee, Wisconsin, USA.|Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Ren
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000453:epidemiology / Q000378:metabolism*; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism*; D063646:Carcinogenesis; D049109:Cell Proliferation; D002478:Cells, Cultured; D004032:Diet; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D008246:Lysophospholipids / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000453:epidemiology / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism; D012306:Risk; D015398:Signal Transduction; D066253:Vascular Remodeling
chemical_list: D018955:CD36 Antigens; D008246:Lysophospholipids; D011960:Receptors, Estrogen; C089212:protein kinase D; D011493:Protein Kinase C; C032881:lysophosphatidic acid
keywords: CD36; lysophosphatidic acid; microvascular remodeling; phospholipid; protein kinase D