Small molecule nAS-E targeting cAMP response element binding protein (CREB) and CREB-binding protein interaction inhibits breast cancer bone metastasis.

ABSTRACT

Bone is the most common metastatic site for breast cancer. The excessive osteoclast activity in the metastatic bone lesions often produces osteolysis. The cyclic-AMP (cAMP)-response element binding protein (CREB) serves a variety of biological functions including the transformation and immortalization of breast cancer cells. In addition, evidence has shown that CREB plays a key role in osteoclastgenesis and bone resorption. Small organic molecules with good pharmacokinetic properties and specificity, targeting CREB-CBP (CREB-binding protein) interaction to inhibit CREB-mediated gene transcription have attracted more considerations as cancer therapeutics. We recently identified naphthol AS-E (nAS-E) as a cell-permeable inhibitor of CREB-mediated gene transcription through inhibiting CREB-CBP interaction. In this study, we tested the effect of nAS-E on breast cancer cell proliferation, survival, migration as well as osteoclast formation and bone resorption in vitro for the first time. Our results demonstrated that nAS-E inhibited breast cancer cell proliferation, migration, survival and suppressed osteoclast differentiation as well as bone resorption through inhibiting CREB-CBP interaction. In addition, the in vivo effect of nAS-E in protecting against breast cancer-induced osteolysis was evaluated. Our results indicated that nAS-E could reverse bone loss induced by MDA-MB-231 tumour. These results suggest that small molecules targeting CREB-CBP interaction to inhibit CREB-mediated gene transcription might be a potential approach for the treatment of breast cancer bone metastasis.