Research Papers:

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

Liuyi Dong, Ye Yuan, Cynthia Opansky, Yiliang Chen, Irene Aguilera-Barrantes, Shiyong Wu, Rong Yuan, Qi Cao, Yee Chung Cheng, Daisy Sahoo, Roy L. Silverstein and Bin Ren _

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Oncotarget. 2017; 8:22550-22562. https://doi.org/10.18632/oncotarget.15123

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Liuyi Dong1,*, Ye Yuan1,2,*, Cynthia Opansky1, Yiliang Chen1, Irene Aguilera-Barrantes3, Shiyong Wu2, Rong Yuan1, Qi Cao4, Yee Chung Cheng5, Daisy Sahoo5, Roy L. Silverstein1,5, Bin Ren1,5

1Blood Research Institute, Blood Center of Wisconsin, Milwaukee, Wisconsin, USA

2Edison Biotechnology Institute and Department of Chemistry and Biochemistry, Ohio University, Athens, Ohio, USA

3Department of Pathology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA

4Diagnostic Radiology and Nuclear Medicine, University of Maryland Medical Center, Baltimore, Maryland, USA

5Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, USA

*These authors contributed equally to this work

Correspondence to:

Bin Ren, email: [email protected]

Keywords: CD36, protein kinase D, phospholipid, lysophosphatidic acid, microvascular remodeling

Received: September 09, 2016     Accepted: January 24, 2017     Published: February 06, 2017


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.

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