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  • Review Article
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Endocrine-responsive breast cancer and strategies for combating resistance

Nature Reviews Cancer volume 2, pages 101–112 (2002)Cite this article

Key Points

  • Breast cancer is the most common cancer of women in the western world. In most cases, breast cancer is oestrogen dependent, and treatment with oestrogen antagonists that inhibit oestrogen receptor (ER) action, particularly tamoxifen, has contributed to a dramatic reduction in breast cancer mortality. However, a substantial proportion of patients presenting with localized disease, and all of the patients with metastatic disease, become resistant to endocrine therapies.

  • In most cases, the ER is present in resistant tumours, and in many of these its activity continues to regulate tumour growth.

  • Resistance to endocrine therapy potentially arises by: ER activation in the absence of oestrogen; hypersensitivity of ER to low levels of circulating oestrogens; or ER activation, rather than inhibition, by oestrogen antagonists.

  • At the molecular level, mechanisms responsible for resistance include:

  • ER mutations that result in increased sensitivity to ligand and/or co-activator recruitment, and a resultant increase in ER activity.

  • Post-translational modifications that result in ligand-independent activation of the ER. These modifications can be triggered by the oncogenic activation of growth-factor signalling pathways.

  • Increased expression of the co-activator proteins that mediate ER activity. By contrast, downregulation of corepressor activity reduces the inhibitory potential of tamoxifen.

  • Mitogenic and anti-apoptotic effects can be mediated by non-genomic effects of the ER, through direct interaction with key components of several signal-transduction pathways. Altered activity of these pathways could contribute to resistance.

  • By understanding which of these pathways could be involved in mediating resistance, we might be able to develop strategies for overcoming or bypassing such resistance.

Abstract

Deaths from breast cancer have fallen markedly over the past decade due, in part, to the use of endocrine agents that reduce the levels of circulating oestrogens or compete with oestrogen for binding to its receptor. However, many breast tumours either fail to respond or become resistant to endocrine therapies. By understanding the mechanisms that underlie this resistance, we might be able to develop strategies for overcoming or bypassing it.

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Figure 1: Structure of normal and malignant breast tissue.
Figure 2: Mechanisms of action of therapeutic agents used in endocrine therapy.
Figure 3: Treatment regimes for oestrogen-receptor-positive breast cancer.
Figure 4: Mechanisms of oestrogen-receptor activation.
Figure 5: Structure of the oestrogen-receptor ligand-binding domain.
Figure 6: Post-translational modification of the oestrogen receptor.
Figure 7: Non-genomic actions of the oestrogen receptor.

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Acknowledgements

We thank L. Buluwela and C. Palmieri for helpful discussions and M. Slade for ER staining slides. We also thank G. Greene for ER LBD structures. We apologize to those whose work could not be cited due to space constraints.

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Authors and Affiliations

  1. Department of Cancer Medicine and Cancer Research Campaign Laboratories, Faculty of Medicine, Imperial College of Science, Technology & Medicine, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK

    Simak Ali & R. Charles Coombes

  2. Simak Ali & R. Charles Coombes

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DATABASES

CancerNet:

breast cancer

glioblastoma

prostate cancer

 LocusLink:

AKT

aromatase

casein kinase II

catechol O-methyltransferase

CBP

CDK2

CDK4

CDK6

CDK7

cyclin D1

cyclin E

COX-2

EGF

EGFR

ERα

ERβ

ERBB2

ERK1

ERK2

GRB2

HDACs

heregulin

IGF-1

IL-6

LHRH

NCOA1

NCOA2

NCOA3

NCOR1

NCOR2

oncostatin M

p300

PCAF

PI3K

progesterone receptor

protein kinase A

PTEN

RAF

RAS

RSK

TFIIH

TRAP

 Medscape DrugInfo:

goserelin

Herceptin

raloxifene

tamoxifen

FURTHER INFORMATION

Breast Cancer Information Core

Nature Medicine special focus on breast cancer

NIH Biology of the Mammary Gland

Glossary

INVOLUTION

Restoration of the normal size of an organ.

END BUD

Epithelial structures from which the milk-producing alveoli of the mammary gland develop during pregnancy.

MESENCHYME

Embryonic tissue composed of loosely organized, unpolarized cells of both mesodermal and ectodermal (for example, neural crest) origin, with a proteoglycan-rich extracellular matrix.

OSTEOBLASTS

Cells that reside in bone, where they are responsible for depositing the bone matrix.

CHONDROCYTES

Cells that produce cartilage.

CYTOCHROME P450 ENZYME COMPLEX

Haem-containing enzymes that oxidize small molecules, including many carcinogens.

ADJUVANT THERAPY

Therapy given in addition to the primary form of treatment — for example, after surgery.

MICROMETASTASES

Clinically undetectable secondary tumours.

ZINC FINGER

A protein module in which conserved cysteine or histidine residues coordinate a zinc atom. Some zinc-finger regions bind specific DNA sequences; others are involved in protein–protein interactions.

GENERAL TRANSCRIPTION MACHINERY

A set of protein complexes, including RNA polymerase II, that are absolutely required for the initiation of mRNA synthesis and that are sufficient for low-level initiation of mRNA synthesis, at least in vitro.

HISTONE ACETYLTRANSFERASE

An enzyme that catalyses the addition of acetyl groups to lysine residues on the amino-terminal tails of histones. Histone acetylation leads to chromatin decondensation and increased rates of transcriptional initiation.

HISTONE DEACETYLASE

An enzyme that catalyses the removal of acetyl groups from lysine residues on the amino-terminal tails of histones. Histone deacetylation leads to chromatin condensation and decreased rates of transcriptional initiation.

BASAL TRANSCRIPTION FACTORS

A set of protein complexes that associate with RNA polymerase II during the initiation of all mRNA synthesis. Sometimes called general transcription factors.

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Ali, S., Coombes, R. Endocrine-responsive breast cancer and strategies for combating resistance. Nat Rev Cancer 2, 101–112 (2002). https://doi.org/10.1038/nrc721

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