Bazedoxifene exhibits antiestrogenic activity in animal models of tamoxifen-resistant breast cancer: Implications for treatment of advanced disease

Suzanne E. Wardell, Erik R. Nelson, Christina A. Chao, Donald P. McDonnell

Research output: Contribution to journalArticle

Abstract

Purpose: There is compelling evidence to suggest that drugs that function as pure estrogen receptor (ER-α) antagonists, or that downregulate the expression of ER-α, would have clinical use in the treatment of advanced tamoxifen- and aromatase-resistant breast cancer. Although such compounds are currently in development, we reasoned, based on our understanding of ER-α pharmacology, that there may already exist among the most recently developed selective estrogen receptor modulators (SERM) compounds that would have usage as breast cancer therapeutics. Thus, our objective was to identify among available SERMs those with unique pharmacologic activities and to evaluate their potential clinical use with predictive models of advanced breast cancer. Experimental Design: A validated molecular profiling technology was used to classify clinically relevant SERMs based on their impact on ER-α conformation. The functional consequences of these observed mechanistic differences on (i) gene expression, (ii) receptor stability, and (iii) activity in cellular and animal models of advanced endocrine-resistant breast cancer were assessed. Results: The high-affinity SERM bazedoxifene was shown to function as a pure ER-α antagonist in cellular models of breast cancer and effectively inhibited the growth of both tamoxifen-sensitive and -resistant breast tumor xenografts. Interestingly, bazedoxifene induced a unique conformational change in ER-α that resulted in its proteasomal degradation, although the latter activity was dispensable for its antagonist efficacy. Conclusion: Bazedoxifene was recently approved for use in the European Union for the treatment of osteoporosis and thus may represent a near-term therapeutic option for patients with advanced breast cancer.

Original languageEnglish (US)
Pages (from-to)2420-2431
Number of pages12
JournalClinical Cancer Research
Volume19
Issue number9
DOIs
StatePublished - May 1 2013
Externally publishedYes

Fingerprint

Tamoxifen
Animal Models
Selective Estrogen Receptor Modulators
Breast Neoplasms
Estrogen Receptors
Aromatase
European Union
Therapeutics
bazedoxifene
Heterografts
Osteoporosis
Research Design
Down-Regulation
Pharmacology
Technology
Gene Expression
Growth
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Bazedoxifene exhibits antiestrogenic activity in animal models of tamoxifen-resistant breast cancer : Implications for treatment of advanced disease. / Wardell, Suzanne E.; Nelson, Erik R.; Chao, Christina A.; McDonnell, Donald P.

In: Clinical Cancer Research, Vol. 19, No. 9, 01.05.2013, p. 2420-2431.

Research output: Contribution to journalArticle

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