Proto-oncogene Tyrosine-protein Kinase Src Links Lipogenesis Via Lipin-1 To Breast Cancer Proliferation

Many studies have shown that increased lipogenesis is associated with an increased risk of cancer as well as its poor prognosis.Breast cancer,one of the most common cancer in the world,is famous for the particularity of its microenvironment that stongly influenced by a large number of adipocytes.However,the underlying mechanism by which the microenvironment and breast cancer are connected has not been clearly defined.The phosphatidic acid phosphatase lipin-1 is the enzyme that catalyzes the reaction to convertphophatidic acid to diacylglycerol.In this thesis,we show that lipin-1 interacts with the Src,the notorious proto-oncogenic protein tyrosine kinase,and is a direct substrate of Src.We found that obesity-related microenvironmental factors and other growth factors,such as epidermal growth factor,platelet-derived growth factor,insulin-like growth factors stimulate the activational phosphorylation of Src,which in turn boost up Src-mediated lipin-1 phosphorylation on Tyr398,Tyr413,and Tyr795 residues.Tyrosine phosphorylation of lipin-1 significantly increases its phosphatidic acid phosphatase(PAP)activity and accelerates the synthesis of phospholipids and triacylglycerols.Importantly,when three tyrosine residues on Src are mutated to phenylalanine,Src is unable to phosphoryate lipin-1,thus failing to promote triacylglycerol synthesis,cell proliferation,and xenograft growth.These results demonstrate that Src directly raise lipogenesis in breast cancer cells upon stimulation from tumor microenvironment,providing a mechanistic link between lipid metabolism and breast cancer propagation.