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Biological determinants of endocrine resistance in breast cancer

Key Points

  • Endocrine therapies that target oestrogen action (anti-oestrogens and aromatase inhibitors) are widely used and successful breast cancer therapies, but many women treated with these therapies will relapse with endocrine-resistant disease.

  • Mechanisms of endocrine resistance in oestrogen receptor (ER)-positive breast cancers include loss of ERα expression and expression of truncated isoforms of ERα and ERβ, post-translational modifications of ERα, increased AP1 activity and deregulation of ER co-activators, increased receptor tyrosine kinase signalling leading to the activation of the Erk and PI3K pathways, and deregulation of the cell cycle and apoptotic machinery.

  • Gene expression signatures that are predictive of poor outcome in women treated with tamoxifen commonly contain ER target genes, as well as genes involved in proliferation, apoptosis, and invasion and metastasis. Many of these signatures are also predictive of outcome in women who have not been treated with tamoxifen and so are markers of intrinsic biology rather than specific to tamoxifen responsiveness.

  • Gene expression signatures representing particular biological processes (for example, cell cycle progression, cell death and invasion) or pathways (for example, RB deregulation, MYC overexpression and E2f activation) can also predict outcome in women treated with tamoxifen and point towards possible mechanisms for endocrine resistance.

  • Functional genetic screens have successfully identified several genes, the loss or overexpression of which can reduce anti-oestrogen sensitivity in cell lines and is associated with clinical endocrine resistance.

  • Insights into the mechanisms of resistance have suggested possible therapeutic approaches for endocrine-resistant ER-positive breast cancer, for example tyrosine kinase inhibitors. Further potential therapeutic targets may emerge from combining large-scale genomic and transcriptomic data with large-scale functional analyses.

Abstract

Endocrine therapies targeting oestrogen action (anti-oestrogens, such as tamoxifen, and aromatase inhibitors) decrease mortality from breast cancer, but their efficacy is limited by intrinsic and acquired therapeutic resistance. Candidate molecular biomarkers and gene expression signatures of tamoxifen response emphasize the importance of deregulation of proliferation and survival signalling in endocrine resistance. However, definition of the specific genetic lesions and molecular processes that determine clinical endocrine resistance is incomplete. The development of large-scale computational and genetic approaches offers the promise of identifying the mediators of endocrine resistance that may be exploited as potential therapeutic targets and biomarkers of response in the clinic.

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Figure 1: Oestrogen action at the molecular level.
Figure 2: Anti-oestrogen action on the cell cycle and apoptotic pathways.
Figure 3: Molecular mechanisms of endocrine resistance.

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Acknowledgements

We are grateful to R. J. Daly, C. E. Caldon and A. J. Butt for helpful discussions and comments, and C. E. Caldon for expert assistance with the figures. Research in the authors' laboratories is supported by the National Health and Medical Research Council of Australia, the Cancer Institute New South Wales, the Australian Cancer Research Foundation, the Petre Foundation and the RT Hall Trust.

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DATABASES

National Cancer Institute Drug Dictionary 

adriamycin

erlotinib

everolimus

gefitinib

lapatinib

tamoxifen

temsirolimus

FURTHER INFORMATION

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Glossary

Aromatase inhibitors

Drugs that function by blocking aromatase, the enzyme that converts androgens to oestrogens in tissues including the breast and adipose tissue. Examples include anastrazole, letrozole and exemestane.

ER-positive breast cancers

In current clinical practice, ERpositive breast cancers are those with immunohistochemically detectable ERα levels.

Adjuvant therapy

A drug treatment (for example, chemotherapy or endocrine therapy) that is given after the primary therapy (for example, surgery and/or radiotherapy), with the aim of increasing the overall effectiveness of treatment.

SERMs

Drugs such as tamoxifen that bind the oestrogen receptor and thereby block the effects of oestrogen on tissues such as the breast but that function similarly to oestrogen in other tissues such as bone. Unlike oestrogen, these drugs are not steroidal in structure.

'Pure' anti-oestrogens

Drugs that bind the oestrogen receptor, thereby blocking the effect of oestrogen, but have no detectable oestrogen-like effects. Most have a steroidal structure.

Intrinsic resistance

The failure to respond to initial drug therapy.

Cytochrome P450 2D6 (CYP2D6)

A member of the large and diverse superfamily of cytochrome P450 enzymes. CYP2D6 catalyses the conversion of tamoxifen into its active metabolites, endoxifen and 4-hydroxytamoxifen. It is highly polymorphic, so its activity is variable between individuals.

Acquired resistance

In contrast to intrinsic resistance, an initial response to drug therapy followed by subsequent disease progression.

Neoadjuvant

A drug treatment that is given weeks to months before surgery, often to reduce the size of tumours before surgery.

Cyclin E1

Cyclin E1 and cyclin E2 are regulatory subunits of kinase complexes that contain CDK2 as their catalytic subunit and regulate the G1 to S phase cell cycle transition.

Cyclin D1

The regulatory subunit of a kinase complex that functions as a growth factor sensor to regulate G1 phase cell cycle progression. The catalytic subunits of cyclin D1-dependent kinases are CDK4 and CDK6.

Bcl-2 family

A protein family of up to 25 members that are classified according to their structure and function as anti-apoptotic (BCL2-like) or pro-apoptotic (multidomain BAX-like and 'BH3-only') proteins.

Autophagy

A cellular response in which the cell metabolizes its own contents and organelles to maintain energy production, often in response to stressful stimuli. Although such a process can eventually result in cell death, it can also be used to maintain cell survival.

Unfolded protein response

A cellular response to stress that senses the misfolding of proteins in the endoplasmic reticulum. It activates a series of pathways that help the cells survive proteotoxicity that is caused by unfolded proteins or activate mechanisms of cell death.

Concordant

Clinical biomarkers and signatures are concordant if they classify the same patients as 'high risk'.

Multivariate analysis

A statistical analysis of the relationship between multiple parameters (variables) to identify those that have a dominant effect on outcome (termed independent predictors of outcome) and those that are dependant or redundant.

Biological concepts analysis

A bioinformatic approach in which related information is grouped together into a 'biological concept', and associations between different 'concepts' are sought.

Synthetic lethal

In genetics, a phenomenon in which the combination of two otherwise non-lethal mutations results in an inviable cell. Used in the context of functional screens to indicate a screen in which the end point is apparent in only some conditions, for example in the presence of a specific genetic lesion.

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Musgrove, E., Sutherland, R. Biological determinants of endocrine resistance in breast cancer. Nat Rev Cancer 9, 631–643 (2009). https://doi.org/10.1038/nrc2713

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