Human haptoglobin contributes to breast cancer oncogenesis through glycolytic activity modulation

Cellular metabolism reprogramming is a hallmark in cancers including breast cancer. Switching off the glycolytic energy in cancer has been indicated as one of the anti-cancer strategies. Aberrant haptoglobin (HP) expression has been shown to cause metabolic dysfunction and implicated in different malignancies. However, its roles in breast cancer and glycolysis remain elusive. Here, we reported HP was upregulated in breast cancer tissues and the circulation. HP conferred oncogenic roles by regulating cell cycle progression and apoptosis in breast cancer cells. Further analysis identified the correlation between HP and glycolytic enzymes such as glucose-6-phosphate isomerase (GPI) and hexokinase (HK). Glycolytic activities were altered upon HP knockdown which were confirmed by glucose uptake and LDH activity assays. GPI was found to be downstream effector of HP while knockdown of GPI led to decreased glycolytic activity and restored oxygen consumption. GPI silencing decreased cell migration/invasion ability and sensitized breast cancer cells to chemo-drug. Moreover, animal study suggested inhibition of both HP and GPI significantly impeded tumor growth in mice. Collectively, we report for the first time the oncogenic roles of HP, at least partially, through regulating glycolysis and its downstream effector, GPI, contributes in maintaining EMT and chemoresistance in breast cancer.