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


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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 epithelialmesenchymal 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 Twistoverexpressing 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 level/activity 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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