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Aromatase inhibitors for breast cancer: lessons from the laboratory

Key Points

  • Aromatase inhibitors act through pure oestrogen deprivation to achieve an endocrine response in oestrogen receptor (ER)-positive breast cancer.

  • Both experimental and clinical data now confirm that aromatase inhibitors achieve greater responses compared with the non-steroidal ER antagonist tamoxifen. This difference might be related to the partial agonist effects of tamoxifen, which can limit its clinical effectiveness.

  • Aromatase activity in peripheral tissues and local malignant and normal breast tissue supplies breast cancer cells with the oestrogen that stimulates cancer growth. The molecular control of this process in breast cancer seems to involve increased COX2 expression.

  • High plasma oestradiol levels are now known to be associated with an increased risk of breast cancer in postmenopausal women. So, use of aromatase inhibitors might provide a novel prevention strategy in the future.

  • Clinical trials have confirmed that aromatase inhibitors are more effective and better tolerated than tamoxifen in postmenopausal women with early or advanced ER-positive breast cancer. As such, aromatase inhibitors are set to replace tamoxifen as the standard of care for these patients.

  • In ER-positive breast carcinomas that co-express the growth-factor receptors EGFR and/or ERBB2, oestrogen deprivation might be more effective than tamoxifen at inhibiting tumour growth. This is consistent with emerging data that confirm cross-talk between growth-factor-receptor and steroid-receptor pathways that leads to tamoxifen resistance as a result of an increased agonist response.

  • Acquisition of resistance during long-term oestrogen deprivation might also involve cross-talk pathways. ER expression might be increased in these cells, with receptors becoming activated and hypersensitive to low residual levels of oestradiol. Strategies to prevent this occurring with various signal-transduction inhibitors and oestrogen-receptor downregulators are now being tested.

Abstract

Endocrine therapy with tamoxifen has been the mainstay of treatment for hormone-sensitive breast cancer for more than 20 years. An alternative strategy of oestrogen deprivation in postmenopausal women with aromatase inhibitors is set to replace tamoxifen based on better efficacy and a delay in the emergence of endocrine resistance. There are fundamental differences in how tamoxifen and aromatase inhibitors alter oestrogen-receptor signalling. Understanding the response and resistance to these different therapies is central to further improving therapeutic options for women with breast cancer.

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Figure 1: Mechanism of action of aromatase inhibitors and tamoxifen.
Figure 2: Molecular effects of tamoxifen and oestrogen deprivation on oestrogen receptor.
Figure 3: Endocrine treatment of xenografts.
Figure 4: Control of aromatase expression in breast carcinomas.
Figure 5: Molecular structures of aromatase inhibitors in clinical use.
Figure 6: Side effects of anastrozole compared with tamoxifen.
Figure 7: Signalling pathways between cell-surface growth-factor receptors and nuclear oestrogen receptor.

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Acknowledgements

We are grateful to L. A. Martin for allowing us to modify her original of Figure 7.

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DATABASES

Cancer.gov

breast cancers

endometrial cancer

LocusLink

AIB1

AKT

COX2

CYP19

EGFR

ERBB2

ERBB3

ERα

ERβ

FOS

JUN

p38 MAPK

phosphatidylinositol 3-kinase

Glossary

OESTROGEN RECEPTOR

The human oestrogen receptor exists in the nucleus of the cell and is bound to heat-shock proteins. It is activated following the binding of a ligand (for example, oestrogen), and subsequently forms dimers within the nucleus at specific oestrogen-response elements in DNA upstream of oestrogen-regulated genes.

HYPOPHYSECTOMY

Surgical removal of the pituitary gland.

THROMBOEMBOLISM

Formation of blood clots in either the arterial or venous system, which might impair the circulation.

SELECTIVE OESTROGEN-RECEPTOR MODULATOR

A drug that binds to the hormone-binding domain of the oestrogen receptor, which induces a specific conformational change that either inhibits or activates transcription of some oestrogen-regulated genes, depending on the gene and/or the tissue context.

OESTROGEN-RESPONSE ELEMENT

A specific DNA sequence that is upstream of oestrogen-regulated genes and that is recognized by the DNA-binding domain of the liganded oestrogen-receptor dimers.

DISEASE-FREE SURVIVAL

Continued survival in the absence of recurrent or new malignancy.

BONE-RESORPTION MARKERS

Serum or urine biomarkers of bone turnover that might be surrogates for accelerated bone breakdown.

TUMOUR RESPONSE RATE

The percentage of tumours that regress in response to a given drug therapy, with tumour shrinkage of at least 50% or more.

AP-1

Activator protein-1 transcription complex, comprised primarily of c-JUN and c-FOS protein dimers and activated by either mitogen-activated protein kinase or pathways of oxidative stress.

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Johnston, S., Dowsett, M. Aromatase inhibitors for breast cancer: lessons from the laboratory. Nat Rev Cancer 3, 821–831 (2003). https://doi.org/10.1038/nrc1211

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