The Effect of Sodium Glucose Transporter 2 Inhibitors on Proliferation and Growth Factor Signaling Pathways in Triple Negative Breast Cancer

Abstract

Triple negative breast cancer (TNBC) is an aggressive form of breast cancer that does not express the estrogen receptor, progesterone receptor, and the HER2 receptor. Since it does not express these receptors, TNBC does not respond to many of the standard therapies for breast cancer. To decrease the number of deaths associated with breast cancer, we must identify therapeutic strategies that effectively prevent the growth and progression of TNBC. Recent studies from our laboratory and others show that the sodium glucose transporter 2 (SGLT2) inhibitor canagliflozin reduces proliferation of human prostate cancer cell lines. To determine whether SGLT2 inhibitors can also suppress TNBC growth, we tested the effect of canagliflozin and other SGLT2 inhibitors on proliferation and protein expression within the BT‐549 human breast cancer cells. Presto Blue assays revealed that two SGLT2 inhibitors, canagliflozin and ipragliflozin, significantly inhibited BT‐549 cell proliferation. However, the SGLT2 inhibitor empagliflozin produced little to no change in cell proliferation. We next examined the effect of SGLT2 inhibitors on Akt and Erk ½ MAP kinase, two proteins that promote TNBC growth. Western blot analysis revealed that canagliflozin reduced phosphorylation of Akt and Erk ½ within BT‐549 cells. Therefore, the ability of canagliflozin to block BT‐549 proliferation may be due in part to canagliflozin‐mediated decreases in Akt and Erk activity. The epidermal growth factor receptor (EGFR) activates both Akt and Erk ½ signaling in BT‐549 cells. To determine whether inhibition of EGFR signaling would alter the response to canagliflozin, we tested the combined effect of canagliflozin and EGFR inhibitors on BT‐549 cell proliferation. Canagliflozin alone was more effective at reducing BT‐549 cell proliferation than the EGFR inhibitors gefitinib and lapatinib. However, the combined effect of canagliflozin and gefitinib as well as the combined effect of canagliflozin and lapatinib was greater than that produced by either compound alone. These data suggest that combination treatments involving canagliflozin and EGFR inhibitors may serve as an effective therapy for patients with TNBC.Support or Funding InformationNIH grant 5T34GM007663This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.