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Molecular Pharmacology

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Research ArticleArticle

The Selective Estrogen Receptor Modulator Bazedoxifene Inhibits Hormone-Independent Breast Cancer Cell Growth and Down-Regulates Estrogen Receptor α and Cyclin D1

Joan S. Lewis-Wambi, Helen Kim, Ramona Curpan, Ronald Grigg, Mohammed A. Sarker and V. Craig Jordan
Molecular Pharmacology October 2011, 80 (4) 610-620; DOI: https://doi.org/10.1124/mol.111.072249
Joan S. Lewis-Wambi
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Helen Kim
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Ramona Curpan
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Ronald Grigg
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Mohammed A. Sarker
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V. Craig Jordan
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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 G1 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 G1 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.

Footnotes

  • ↵Embedded Image The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.

  • This work was supported by the National Institutes of Health National Cancer Institute [Grants K01-CA12005101A2, P30-CA006927]; the American Cancer Society [Grant IRG-9202714]; the Department of Defense [Grant BC050277]; and the National University Research Council of Romania-CNCSIS-UEFISCU [Grant PN-II-PCE-ID1268].

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    doi:10.1124/mol.111.072249.

  • ABBREVIATIONS:

    BZA
    bazedoxifene acetate
    ER
    estrogen receptor
    SERM
    selective estrogen receptor modulator
    TAM
    tamoxifen
    RAL
    raloxifene
    E2
    17β-estradiol
    FUL
    fulvestrant
    siRNA
    small interfering RNA
    4OHT
    4-hydroxytamoxifen
    ENDOX
    endoxifen
    Luc
    luciferase
    ERE
    estrogen response element
    PCR
    polymerase chain reaction
    RT-PCR
    reverse transcriptase-polymerase chain reaction
    IFD
    Induced Fit Docking
    SRC
    steroid receptor coactivator
    ICI 182,780
    fulvestrant
    MG132
    N-benzoyloxycarbonyl (Z)-Leu-Leu-leucinal
    PDB
    Protein Data Bank.

  • Received March 14, 2011.
  • Accepted July 7, 2011.
  • Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 80 (4)
Molecular Pharmacology
Vol. 80, Issue 4
1 Oct 2011
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Research ArticleArticle

Bazedoxifene Inhibits Endocrine-Resistant Breast Cancer

Joan S. Lewis-Wambi, Helen Kim, Ramona Curpan, Ronald Grigg, Mohammed A. Sarker and V. Craig Jordan
Molecular Pharmacology October 1, 2011, 80 (4) 610-620; DOI: https://doi.org/10.1124/mol.111.072249

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Research ArticleArticle

Bazedoxifene Inhibits Endocrine-Resistant Breast Cancer

Joan S. Lewis-Wambi, Helen Kim, Ramona Curpan, Ronald Grigg, Mohammed A. Sarker and V. Craig Jordan
Molecular Pharmacology October 1, 2011, 80 (4) 610-620; DOI: https://doi.org/10.1124/mol.111.072249
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