Understanding the mechanisms of aromatase inhibitor resistance

Abstract

Aromatase inhibitors (AIs) have a central role in the treatment of breast cancer; however, resistance is a major obstacle to optimal management. Evidence from endocrine, molecular and pathological measurements in clinical material taken before and after therapy with AIs and data from clinical trials in which AIs have been given as treatment either alone or in combination with other targeted agents suggest diverse causes for resistance. These include inherent tumour insensitivity to oestrogen, ineffective inhibition of aromatase, sources of oestrogenic hormones independent of aromatase, activation of signalling by non-endocrine pathways, enhanced cell survival and selection of hormone-insensitive cellular clones during treatment.

Figure 1

Effects of neoadjuvant treatment with letrozole on changes (within 10 to 14 days) in microarray expression of ribosomal proteins. (a) Average changes for the total group, the responding group and the non-responding group. Error bars represent standard errors of the mean. (b) Changes in individual tumours. Red represents an increase in expression and green a decrease. Brightness of colour indicates degree of change, with the brightest colours representing the greatest change. The RPLP0 gene is represented by four probe sets.

Figure 2

Early changes in microarray expression of oestrogen-regulated genes (KIAA0101, IRS1 (insulin receptor substrate 1), SERPINA3, TFF1 and TFF3 (trefoil factors 1 and 3) and proliferation markers (CDC2, Cyclin B1, CKS2, thymidylate synthase (TYMS), proliferating cell nuclear antigen (PCNA)) associated with neoadjuvant treatment with letrozole in individual breast cancers clinically resistant to endocrine treatment. Red represents an increase in expression and green a decrease. Brightness of colour indicates degree of change, with the brightest colours representing the greatest change. The left-hand column represents an ER-negative tumour (-ve), the A columns illustrate tumours with a molecular resistant phenotype, the B columns cases exhibiting decreases in expression of oestrogen-regulated genes but not in proliferation-related genes, and the C columns tumours showing molecular sensitivity in both oestrogen-regulated and proliferation-related gene expression.

Figure 3

Mechanisms of oestrogen-stimulated growth (whereby androgen is aromatised into oestrogen, which interacts with and activates oestrogen receptor (ER) to stimulate proliferation and growth), aromatase inhibitor (AI)-induced response (whereby AIs block aromatization of androgens into oestrogens) and multiple potential mechanisms of resistance to AIs. Blocks represent sites of specific interactions: A, ineffective inhibition of aromatase; B, alternative sources of oestrogen/oestrogenic hormones (ES); C, inherent oestrogen insensitivity (non-functional ER); D, ligand-independent activation of oestrogen signalling pathways; E, oestrogen signalling disconnected from tumour proliferation and growth; F, enhanced cell survival. Abbreviations: A, androgen precursor; CSF, cell survival factor; E, oestrogen; ER, oestrogen receptor; ER-P, activated (phosphorylated) ER; GF, growth factor; Prolif, proliferation; Resp, response.