Antiestrogen resistance in breast cancer and the role of estrogen receptor signaling

Robert Clarke, Minetta C. Liu, Kerrie B. Bouker, Zhiping Gu, Richard Y. Lee, Yuelin Zhu, Todd Skaar, Bianca Gomez, Kerry O'Brien, Yue Wang, Leena A. Hilakivi-Clarke

Research output: Contribution to journalArticle

333 Citations (Scopus)

Abstract

Antiestrogens include agents such as tamoxifen, toremifene, raloxifene, and fulvestrant. Currently, tamoxifen is the only drug approved for use in breast cancer chemoprevention, and it remains the treatment of choice for most women with hormone receptor positive, invasive breast carcinoma. While antiestrogens have been available since the early 1970s, we still do not fully understand their mechanisms of action and resistance. Essentially, two forms of antiestrogen resistance occur: de novo resistance and acquired resistance. Absence of estrogen receptor (ER) expression is the most common de novo resistance mechanism, whereas a complete loss of ER expression is not common in acquired resistance. Antiestrogen unresponsiveness appears to be the major acquired resistance phenotype, with a switch to an antiestrogen-stimulated growth being a minor phenotype. Since antiestrogens compete with estrogens for binding to ER, clinical response to antiestrogens may be affected by exogenous estrogenic exposures. Such exposures include estrogenic hormone replacement therapies and dietary and environmental exposures that directly or indirectly increase a tumor's estrogenic environment. Whether antiestrogen resistance can be conferred by a switch from predominantly ERα to ERβ expression remains unanswered, but predicting response to antiestrogen therapy requires only measurement of ERα expression. The role of altered receptor coactivator or corepressor expression in antiestrogen resistance also is unclear, and understanding their roles may be confounded by their ubiquitous expression and functional redundancy. We have proposed a gene network approach to exploring the mechanistic aspects of antiestrogen resistance. Using transcriptome and proteome analyses, we have begun to identify candidate genes that comprise one component of a larger, putative gene network. These candidate genes include NFκB, interferon regulatory factor-1, nucleophosmin, and the X-box binding protein-1. The network also may involve signaling through ras and MAPK, implicating crosstalk with growth factors and cytokines. Ultimately, signaling affects the expression/function of the proliferation and/or apoptotic machineries.

Original languageEnglish
Pages (from-to)7316-7339
Number of pages24
JournalOncogene
Volume22
Issue number47 REV. ISS. 6
DOIs
StatePublished - Oct 20 2003

Fingerprint

Estrogen Receptor Modulators
Estrogen Receptors
Breast Neoplasms
Gene Regulatory Networks
Tamoxifen
Toremifene
Interferon Regulatory Factor-1
Phenotype
Co-Repressor Proteins
Hormone Replacement Therapy
Environmental Exposure
Chemoprevention
Gene Expression Profiling
Proteome
Genes
Intercellular Signaling Peptides and Proteins
Estrogens
Hormones
Cytokines

Keywords

  • Coregulator
  • Estrogen receptor
  • Faslodex
  • ICI 182,780
  • Tamoxifen

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Clarke, R., Liu, M. C., Bouker, K. B., Gu, Z., Lee, R. Y., Zhu, Y., ... Hilakivi-Clarke, L. A. (2003). Antiestrogen resistance in breast cancer and the role of estrogen receptor signaling. Oncogene, 22(47 REV. ISS. 6), 7316-7339. https://doi.org/10.1038/sj.onc.1206937

Antiestrogen resistance in breast cancer and the role of estrogen receptor signaling. / Clarke, Robert; Liu, Minetta C.; Bouker, Kerrie B.; Gu, Zhiping; Lee, Richard Y.; Zhu, Yuelin; Skaar, Todd; Gomez, Bianca; O'Brien, Kerry; Wang, Yue; Hilakivi-Clarke, Leena A.

In: Oncogene, Vol. 22, No. 47 REV. ISS. 6, 20.10.2003, p. 7316-7339.

Research output: Contribution to journalArticle

Clarke, R, Liu, MC, Bouker, KB, Gu, Z, Lee, RY, Zhu, Y, Skaar, T, Gomez, B, O'Brien, K, Wang, Y & Hilakivi-Clarke, LA 2003, 'Antiestrogen resistance in breast cancer and the role of estrogen receptor signaling', Oncogene, vol. 22, no. 47 REV. ISS. 6, pp. 7316-7339. https://doi.org/10.1038/sj.onc.1206937
Clarke R, Liu MC, Bouker KB, Gu Z, Lee RY, Zhu Y et al. Antiestrogen resistance in breast cancer and the role of estrogen receptor signaling. Oncogene. 2003 Oct 20;22(47 REV. ISS. 6):7316-7339. https://doi.org/10.1038/sj.onc.1206937
Clarke, Robert ; Liu, Minetta C. ; Bouker, Kerrie B. ; Gu, Zhiping ; Lee, Richard Y. ; Zhu, Yuelin ; Skaar, Todd ; Gomez, Bianca ; O'Brien, Kerry ; Wang, Yue ; Hilakivi-Clarke, Leena A. / Antiestrogen resistance in breast cancer and the role of estrogen receptor signaling. In: Oncogene. 2003 ; Vol. 22, No. 47 REV. ISS. 6. pp. 7316-7339.
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