Mitochondrial phosphoenolpyruvate carboxykinase (PEPCK-M), which is encoded by PCK2, is up-regulated in various tumors, including breast cancer (BC). The role of PEPCK-M in the pathogenesis and progression of BC is largely unknown. Recently, we found that PEPCK-M is differentially expressed in BCs. High expression of PEPCK-M was noted in around half of triple negative BC (TNBC). We evaluated the function of PEPCK-M in TNBC. Knockdown of PCK2 reduced the proliferative rate of TNBC cells and delayed the cell cycle progression to S phase. In addition, knockdown of PCK2 attenuated invasion and migration of TNBC cells with reduced expression of smad3, snail-1 and slug. PCK2 positively regulated smad3 at transcriptional level. Knockdown of smad3 reduced expression of snail-1 and slug. In addition, knockdown of PCK2 attenuated the stimulatory effect of TGF-beta to smad3 phosphorylation in TNBC cells. Taken together, PCK2 not only promotes cell proliferation and cell cycle progression of TNBC but also promotes tumor invasion/migration via regulation of smad3. The result suggests that PEPCK-M may be a potential therapeutic target for the treatment of TNBC.
