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.
Highlights
Breast cancer is the most commonly diagnosed cancer among females.[1]
We described naphthol AS‐E as a cell‐permeable small molecule inhibitors of KIX‐kinase‐inducible domain (KID) interaction to inhibit CREB‐mediated gene transcription based on a renilla luciferase complementation assay in HEK293T cells.[46,47]
To investigate the possibility that phosphorylated CREB (p‐CREB) might participate in naphthol AS‐E (nAS‐E) effect on CREB‐mediated gene transcription, we investigated the effect of nAS‐E on p‐CREB levels in Bone marrow monocytes (BMMs) using WB
Summary
Breast cancer is the most commonly diagnosed cancer among females.[1]. At least 80% of the breast cancer patients will develop bone metastases during the course of their diseases.[2,3] In the metastatic bone lesions, there are complex cross‐talks between metastatic breast cancer cells and bone cells.[4,5,6,7] For example, breast cancer cells produce various secreted factors[8,9,10,11] in the bone microenvironment, which enhance osteoclastogenesis and inhibit osteoblastogenesis, Patients who develop bone metastases suffer from skeletal‐related events (SREs)[12] such as pathological fracture, spinal cord compression, bone pain and hypercalcemia. Biological approaches were pursued to inhibit CREB function in breast cancer cells such as the utilization of dominant‐negative CREB mutants, CREB “decoy” oligonucleotides and RNA interference.[38,39,40,41] clinical applications of these approaches are rather limited since gene therapy techniques would be required.[42] utilizing small organic molecules to prevent breast cancer‐induced bone metastasis and osteolysis could be of great interest due to their better pharmacokinetic properties. It is reported that NSC 12155 and NSC 45576 were identified as inhibitors of CREB‐CRE interaction by high‐throughput screening assay from the NCI‐diversity set of 1900 compounds These compounds are not specific in inhibiting CREB‐CRE interaction.[44] The third strategy is to target CREB‐binding protein (CREB‐ CBP) interaction to inhibit CREB‐mediated gene transcription in breast cancer cells and osteoclasts. Our results highlighted the potential of small molecules targeting CREB‐CBP interaction in the treatment of breast cancer‐induced bone loss
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