@article {Lewis-Wambimol.111.072249, author = {Joan S Lewis-Wambi and Helen R Kim and Ramona Curpan and Ronald Grigg and Mohammed A Sarker and V. Craig Jordan}, title = {The Selective Estrogen Receptor Modulator Bazedoxifene Inhibits Hormone-Independent Breast Cancer Cell Growth and Downregulates Estrogen Receptor α and Cyclin D1}, elocation-id = {mol.111.072249}, year = {2011}, doi = {10.1124/mol.111.072249}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {Bazedoxifene (BZA) is a third generation selective estrogen receptor modulator (SERM) that was recently approved for the prevention and treatment of postmenopausal osteoporosis. It has antitumor activity; however, its mechanism of action remains unclear. In the present study, we characterized the effects of BZA and several other SERMs on the proliferation of hormone-dependent MCF-7 and T47D breast cancer cells and hormone-independent MCF-7:5C and MCF-7:2A cells and examined its mechanism of action in these cells. We found that all of the SERMs inhibited the growth of MCF-7, T47D, and MCF-7:2A cells, however, only BZA and FUL inhibited the growth of hormone-independent MCF-7:5C cells. Cell cycle analysis revealed that BZA and FUL induced G1 blockade in MCF-7:5C cells, however, BZA downregulated cyclin D1 which was constitutively overexpressed in these cells whereas FUL suppressed cyclin A. Further analysis revealed that siRNA knockdown of cyclin D1 reduced the basal growth of MCF-7:5C cells and it blocked the ability of BZA to induce G1 arrest in these cells. BZA also downregulated ERα protein by increasing its degradation and suppressing cyclin D1 promoter activity in MCF-7:5C cells. Lastly, molecular modeling studies demonstrated that BZA bound to ERα in an orientation similar to raloxifene; however, a number of residues adopted different conformations in the IFD docking poses when compared with the experimental structure of ERα-RAL. Together, these findings indicate that BZA is distinct from other SERMs in its ability to inhibit hormone-independent breast cancer cell growth and to regulate ERα and cyclin D1 expression in resistant cells.}, issn = {0026-895X}, URL = {https://molpharm.aspetjournals.org/content/early/2011/07/07/mol.111.072249}, eprint = {https://molpharm.aspetjournals.org/content/early/2011/07/07/mol.111.072249.full.pdf}, journal = {Molecular Pharmacology} }