Metformin suppresses proliferation and invasion of drug-resistant breast cancer cells by activation of the Hippo pathway

Drug resistance limits the clinical efficacy of breast cancer therapies, and overexpression or activation of Yes-associated protein (YAP) is common in drug-resistant cancer cells. Thus, inhibition of YAP may reduce resistance to anti-cancer drugs. Metformin (MET), a first-line diabetes medication that also has anti-tumour activities, induces AMP-activated protein kinase (AMPK), directly phosphorylates YAP and inhibits YAP transcriptional activity. In this study, we determined the effect of MET on the proliferation and invasion of drug-resistant breast cancer cells and then investigated the underlying molecular mechanism. Our in vivo and in vitro experiments indicated that MET suppressed breast cancer by an AMPK-independent pathway to decrease YAP nuclear localization. In drug-sensitive cells, MET activated the Hippo pathway by increasing KIBRA and FRMD6 expression, but this did not occur in drug-resistant cells. Scribble (SCRIB), a cell polarity protein, was notably down-regulated in tamoxifen- and paclitaxel-resistant breast cancer cells relative to sensitive cells. We also found that MET suppressed the proliferation and invasion of drug-resistant breast cancer cells by increasing the expression and cell membrane localization of SCRIB, which enhanced the interaction of SCRIB with MST1 and LATS1, and inhibited YAP nuclear localization and transcriptional activity.