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-␣ (ER␣) 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 ER␣ 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 ER␣-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 ER␣ and cyclin D1 expression in resistant cells.

Nuclear Receptors and Their Selective Pharmacologic Modulators

“…Bazedoxifene antagonizes estrogen-stimulated proliferation of MCF-7 breast cancer cells with little to no effects in uterine and CNS tissue, and also maintains bone density, reduces cholesterol in rats, and causes regression of endometriosis in mice (Komm and Lyttle, 2001;Komm et al, 2005;Ronkin et al, 2005;Kulak et al, 2011). Bazedoxifene inhibits the proliferation of estrogen-dependent (MCF-7 and T47D) and estrogenindependent (MCF-7:5C and MCF-7:2A) cell lines (Lewis-Wambi et al, 2011). Its ability to antagonize growth of MCF-7:5C cells in particular is unique among SERMs and occurs as a result of downregulation of ERa (via protein degradation) and suppressing cyclin D1 expression.…”

The Dual Estrogen ReceptorαInhibitory Effects of the Tissue-Selective Estrogen Complex for Endometrial and Breast Safety

“…The SERMs, BAZ, and tamoxifen inhibit ERa activity in breast cancer cells (Lewis-Wambi et al, 2011;Cirillo et al, 2013). However, these drugs inhibit ERa activity through different mechanisms.…”

Effect of single mutagenesis on the binding pocket of canine estrogen receptor alpha: Structure and binding affinity

“…However, the difference is in the amino acid residues and the site of interaction. These indicated that the shapes of the hERα and cERα binding pockets are different between the two species [23,24] . Among the different key amino acid residues, E354 formed hydrogen bonding with both E2 and bazedoxifene.…”