title: The selective estrogen receptor modulator bazedoxifene inhibits hormone-independent breast cancer cell growth and down-regulates estrogen receptor α and cyclin D1.
abstract: Bazedoxifene (BZA) is a third-generation selective estrogen receptor modulator (SERM) that has been 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 fulvestrant (FUL) inhibited the growth of hormone-independent MCF-7:5C cells. Cell cycle analysis revealed that BZA and FUL induced G(1) blockade in MCF-7:5C cells; however, BZA down-regulated cyclin D1, which was constitutively overexpressed in these cells, whereas FUL suppressed cyclin A. Further analysis revealed that small interfering RNA knockdown of cyclin D1 reduced the basal growth of MCF-7:5C cells, and it blocked the ability of BZA to induce G(1) arrest in these cells. BZA also down-regulated estrogen receptor-α (ERα) protein by increasing its degradation and suppressing cyclin D1 promoter activity in MCF-7:5C cells. Finally, 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 induced-fit docking poses compared with the experimental structure of ERα-raloxifene. 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.
authors: Women's Cancer Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA. joan.lewis@fccc.edu
authors: Joan S
authors: JS
authors: Lewis-Wambi
authors: Helen
authors: H
authors: Kim
authors: Ramona
authors: R
authors: Curpan
authors: Ronald
authors: R
authors: Grigg
authors: Mohammed A
authors: MA
authors: Sarker
authors: V Craig
authors: VC
authors: Jordan
mesh_terms: D001665:Binding Sites / Q000502:physiology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D019938:Cyclin D1 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology*; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D005260:Female; D055785:Gene Knockdown Techniques / Q000379:methods; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D049410:Luciferases, Renilla; D020845:Selective Estrogen Receptor Modulators / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: C530104:CCND1 protein, human; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D007211:Indoles; D020845:Selective Estrogen Receptor Modulators; D019938:Cyclin D1; D049410:Luciferases, Renilla; C447119:bazedoxifene