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Define the Twist-ATX-LPAR1 Signaling Axis in Promoting Obesity Associated Triple Negative Breast Cancer

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University of Kentucky Lexington United States

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Breast cancer remains the second leading cause of cancer related death in women worldwide. Triple negative breast cancer TNBC carries a poorer prognosis, given its higher genomic instability, tendency toward early metastasis, and lack of effective targeted therapies. Obesity is a risk factor for TNBC so understanding the link between TNBC and obesity is crucial to the development of novel prevention and treatment strategies. TNBC activates the epithelial-mesenchymal transition EMT program and a key EMT inducer, the transcription factor Twist is highly expressed in TNBC. Autotaxin ATX and LPAR1 were dramatically increased in Twist-overexpressing breast cancer and adipose cells. Encoded by the ENPP2 gene, ATX is a secreted enzyme that produces most of the extracellular lysophosphatidic acid LPA, which signals through its receptors LPAR16 to mediate a wide range of inflammatory processes including wound healing, fibrosis and metastasis. Adipose is an important source for the synthesis and secretion of ATX, so ATX levelactivity are increased during obesity associated adipose tissue expansion. Accordingly, we propose that Twist activation intensifies the ATXLPAR1 signaling to promote the development and progression of obesityassociated TNBC. We are testing this hypothesis using genetic and pharmacological approaches in cell and animal models of breast cancer.

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Technical Report,15 Apr 2016,14 Apr 2017




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