Cancer Letters

Cancer Letters

Volume 256, Issue 1, 18 October 2007, Pages 1-24
Cancer Letters

Mini-review
Pathways to tamoxifen resistance

https://doi.org/10.1016/j.canlet.2007.03.016Get rights and content

Abstract

Therapies that target the synthesis of estrogen or the function of estrogen receptor(s) have been developed to treat breast cancer. While these approaches have proven to be beneficial to a large number of patients, both de novo and acquired resistance to these drugs is a significant problem. Recent advances in our understanding of the molecular mechanisms that contribute to resistance have provided a means to begin to predict patient responses to these drugs and develop rational approaches for combining therapeutic agents to circumvent or desensitize the resistant phenotype. Here, we review common mechanisms of antiestrogen resistance and discuss the implications for prediction of response and design of effective combinatorial treatments.

Section snippets

Endocrine therapies for breast cancer

Estrogen and the steroid estrogen receptors (ERs) are critical regulators of breast epithelial cell proliferation, differentiation, and apoptosis. Mammals express two ERs, ERα and ERβ, which show distinct tissue distributions and functions (for review, see [1]). Mice with targeted deletions of one or both ER genes have established that ERα is the key regulator of mammary gland development. ERα is expressed in 15–30% of the luminal epithelial cells present in normal breast tissue; estrogen

Molecular mechanisms of antiestrogen resistance

Emerging data from breast tumor biopsies indicate that altered expression and/or modification of several growth factor receptors and downstream signaling molecules correlate with tamoxifen resistance (Fig. 1). Epidermal growth factor receptor (EGFR), human epidermal growth factor receptor type 2 (HER2), and insulin-like growth factor-1 receptor (IGF-1R) signaling pathways are often elevated in non-responsive tumors that exhibit either de novo or acquired resistance [27], [28], [29], [30], as is

Endocrine therapies; effect on motility/invasion/metastasis

Metastatic breast cancer is ultimately the greatest cause of disease mortality. Tamoxifen is beneficial for decreasing secondary disease occurrence, both at local and distant sites [178]. However, the major phenotype of endocrine resistance is cancer recurrence. While clinical data have not definitively linked antiestrogen resistance with metastasis, many of the proteins/pathways discussed above in Section 2 that are involved in circumventing antiestrogen-induced blocks in cell cycle

Prediction of response

It is clear from the discussion above that resistance to endocrine therapy likely occurs through diverse mechanisms that vary from patient to patient. Consequently, it is imperative to develop molecular signatures that can predict the likelihood of response and potential for relapse of individual tumors. Initially, predictive markers for tamoxifen resistance included expression of ER and receptor tyrosine kinases such as EGFR and HER2. As our understanding of antiestrogen resistance has

Acknowledgments

The authors acknowledge support of our research from the Susan G. Komen Breast Cancer Foundation (PDF0503551) and Department of Defense Breast Cancer Research Program (BC051851) to RBR, the Department of Defense Breast Cancer Research Program (BC050339) to RSS, the National Cancer Institute institutional training Grant (T32 CA009109) for R.S.S. and M.S.G.; and the National Institutes of Health (R01 CA 096846) to AHB and R01 CA 123037 to Sarah J. Parsons, AHB Co-PI).

References (216)

  • R. Clarke et al.

    Molecular and pharmacological aspects of antiestrogen resistance

    J. Steroid Biochem. Mol. Biol.

    (2001)
  • A. Sommer et al.

    Studies on the development of resistance to the pure antiestrogen faslodex in three human breast cancer cell lines

    J. Steroid Biochem. Mol. Biol.

    (2003)
  • A. Howell

    Fulvestrant (’faslodex’): current and future role in breast cancer management

    Crit. Rev. Oncol. Hematol.

    (2006)
  • R.I. Nicholson et al.

    Growth factor signalling networks in breast cancer and resistance to endocrine agents: new therapeutic strategies

    J. Steroid Biochem. Mol. Biol.

    (2005)
  • E. Anderson et al.

    Steroid receptors and cell cycle in normal mammary epithelium

    J. Mammary Gland Biol. Neoplasia

    (2004)
  • V. Speirs et al.

    Distinct expression patterns of ER alpha and ER beta in normal human mammary gland

    J. Clin. Pathol.

    (2002)
  • C. Forster et al.

    Involvement of estrogen receptor beta in terminal differentiation of mammary gland epithelium

    Proc. Natl. Acad. Sci. USA

    (2002)
  • S. Saji et al.

    Clinical significance of estrogen receptor beta in breast cancer

    Cancer Chemother. Pharmacol.

    (2005)
  • L.C. Murphy et al.

    Is oestrogen receptor-beta a predictor of endocrine therapy responsiveness in human breast cancer?

    Endocr. Relat. Cancer

    (2006)
  • J. Matthews et al.

    Estrogen receptor (ER) beta modulates ER alpha-mediated transcriptional activation by altering the recruitment of c-fos and c-jun to estrogen-responsive promoters

    Mol. Endocrinol.

    (2006)
  • L.A. Helguero et al.

    Estrogen receptors alpha (ER alpha) and beta (ER beta) differentially regulate proliferation and apoptosis of the normal murine mammary epithelial cell line HC11

    Oncogene

    (2005)
  • F. Stossi et al.

    Transcriptional profiling of estrogen-regulated gene expression via estrogen receptor (ER) alpha or ER beta in human osteosarcoma cells: distinct and common target genes for these receptors

    Endocrinology

    (2004)
  • E.C. Chang et al.

    Impact of estrogen receptor beta on gene networks regulated by estrogen receptor alpha in breast cancer cells

    Endocrinology

    (2006)
  • B. Fisher et al.

    Tamoxifen for prevention of breast cancer: Report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study

    J. Natl. Cancer Inst.

    (1998)
  • G.H. Veeneman

    Non-steroidal subtype selective estrogens

    Curr. Med. Chem.

    (2005)
  • A.U. Buzdar

    TAS-108: a novel steroidal antiestrogen

    Clin. Cancer Res.

    (2005)
  • A. Howell

    Pure oestrogen antagonists for the treatment of advanced breast cancer

    Endocr. Relat. Cancer

    (2006)
  • C.K. Osborne et al.

    Fulvestrant: an oestrogen receptor antagonist with a novel mechanism of action

    Br. J. Cancer

    (2004)
  • R.W. Brueggemeier

    Update on the use of aromatase inhibitors in breast cancer

    Expert Opin. Pharmacother.

    (2006)
  • S.F. Doisneau-Sixou et al.

    Additive effects of tamoxifen and the farnesyl transferase inhibitor FTI-277 on inhibition of MCF-7 breast cancer cell-cycle progression

    Int. J. Cancer

    (2003)
  • A. Thiantanawat et al.

    Signaling pathways of apoptosis activated by aromatase inhibitors and antiestrogens

    Cancer Res.

    (2003)
  • K.B. Bouker et al.

    Interferon regulatory factor-1 mediates the proapoptotic but not cell cycle arrest effects of the steroidal antiestrogen ICI 182,780 (faslodex, fulvestrant)

    Cancer Res.

    (2004)
  • S.F. Doisneau-Sixou et al.

    Estrogen and antiestrogen regulation of cell cycle progression in breast cancer cells

    Endocr. Relat. Cancer

    (2003)
  • G. Arpino et al.

    HER-2 amplification, HER-1 expression, and tamoxifen response in estrogen receptor-positive metastatic breast cancer: a Southwest Oncology Group Study

    Clin. Cancer Res.

    (2004)
  • J.M. Gee et al.

    Epidermal growth factor receptor/HER2/insulin-like growth factor receptor signalling and oestrogen receptor activity in clinical breast cancer

    Endocr. Relat. Cancer

    (2005)
  • M. Dowsett et al.

    Growth factor signalling and response to endocrine therapy: The Royal Marsden Experience

    Endocr. Relat. Cancer

    (2005)
  • M.C. Gutierrez et al.

    Molecular changes in tamoxifen-resistant breast cancer: relationship between estrogen receptor, HER-2, and p38 mitogen-activated protein kinase

    J. Clin. Oncol.

    (2005)
  • T. Kirkegaard et al.

    AKT activation predicts outcome in breast cancer patients treated with tamoxifen

    J. Pathol.

    (2005)
  • C. Holm et al.

    Association between Pak1 expression and subcellular localization and tamoxifen resistance in breast cancer patients

    J. Natl. Cancer Inst.

    (2006)
  • S. van der Flier et al.

    BCAR1/p130Cas protein and primary breast cancer: prognosis and response to tamoxifen treatment

    J. Natl. Cancer Inst.

    (2000)
  • C.K. Osborne et al.

    Role of the estrogen receptor coactivator AIB1 (SRC-3) and HER-2/neu in tamoxifen resistance in breast cancer

    J. Natl. Cancer Inst.

    (2003)
  • N. Sarwar et al.

    Phosphorylation of ER alpha at serine 118 in primary breast cancer and in tamoxifen-resistant tumours is indicative of a complex role for ER alpha phosphorylation in breast cancer progression

    Endocr. Relat. Cancer

    (2006)
  • E. Cannings et al.

    Bad expression predicts outcome in patients treated with tamoxifen

    Breast Cancer Res. Treat.

    (2007)
  • S.P. Linke et al.

    A multimarker model to predict outcome in tamoxifen-treated breast cancer patients

    Clin. Cancer Res.

    (2006)
  • G.G. Kuiper et al.

    Cloning of a novel receptor expressed in rat prostate and ovary

    Proc. Natl. Acad. Sci. USA

    (1996)
  • D.P. McDonnell

    The molecular determinants of estrogen receptor pharmacology

    Maturitas

    (2004)
  • K. Paech et al.

    Differential ligand activation of estrogen receptors ER alpha and ER beta at AP1 sites

    Science

    (1997)
  • A. Zou et al.

    Estrogen receptor beta activates the human retinoic acid receptor alpha-1 promoter in response to tamoxifen and other estrogen receptor antagonists, but not in response to estrogen

    Mol. Endocrinol.

    (1999)
  • C.L. Smith et al.

    Coregulator function: a key to understanding tissue specificity of selective receptor modulators

    Endocr. Rev.

    (2004)
  • J.M. Hall et al.

    Coregulators in nuclear estrogen receptor action: from concept to therapeutic targeting

    Mol. Interv.

    (2005)
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