What do we know about the mechanisms of aromatase inhibitor resistance?

Abstract

Clinical trials have demonstrated the importance of aromatase inhibitor (AI) therapy in the effective treatment of hormone-dependent breast cancers. Yet, as with all prolonged drug therapy, resistance to aromatase inhibitors does develop. To date, the precise mechanism responsible for resistance to aromatase inhibitors is not completely understood. In this paper, several mechanisms of de novo/ intrinsic resistance and acquired resistance to AIs are discussed. These mechanisms are hypothesized based on important findings from a number of laboratories.To better understand this question, our lab has generated, in vitro, breast cancer cell lines that are resistant to aromatase inhibitors. Resistant cell lines were generated over a prolonged period of time using the MCF-7aro (aromatase overexpressed) breast cancer line. These cell lines are resistant to the aromatase inhibitors letrozole, anastrozole and exemestane and the anti-estrogen tamoxifen, for comparison. Two types of resistant cell lines have been generated, those that grow in the presence of Testosterone (T) which is needed for cell growth, and resistant lines that are cultured in the presence of inhibitor only (no T). In addition to functional characterization of aromatase and ERα in these resistant cell lines, microarray analysis has been employed in order to determine differential gene expression within the aromatase inhibitor resistant cell lines versus tamoxifen, in order to better understand the mechanism responsible for AI resistance on a genome-wide scale. We anticipate that our studies will generate important information on the mechanisms of AI resistance. Such information can be valuable for the development of treatment strategies against AI resistant breast cancers.

Transient over-expression of estrogen receptor-α in breast cancer cells promotes cell survival and estrogen-independent growth

“…Aromatase inhibitors act by preventing the conversion of androgens into estrogens by the aromatase enzyme, with new aromatase inhibitors displaying greater efficacy than tamoxifen. However, resistance to aromatase inhibitors also develops in many cases [3,4].…”

New experimental models for aromatase inhibitor resistance

“…In contrast to AI/tamoxifen-responsive cells, cell proliferation assays demonstrate that the AIresistant cell lines all proliferated similarly to the testosterone control, implying that these cells had adapted a mechanism to grow despite the presence of the inhibitor [35]. The time to generate the different resistant cell lines varied among different inhibitors.…”

“…Exemestane induces aromatase degradation in a dose-responsive manner (25 to 200 nM), and the effect can be seen in as early as 2 hours. Metabolic labeling with 35 S-methionine was used to determine the half-life of aromatase protein. In the presence of 200 nM exemestane, the half-life of aromatase was reduced to 12.5 hours, compared to 28.2 hours in the untreated cells.…”

“…LTED cells have been generated in Dr. R. Santen's, Dr. M. Dowsett's, Dr. R. Nicholson's and Dr. A. Brodie's laboratories [31][32][33][34]. The key findings from these laboratories have been reviewed in a recent report [35]. Briefly, studies from these laboratories have revealed that growth factor pathways are activated in these estrogen withdrawal cell lines, namely HER2 and IGF-1R.…”

“…To check the quality of our microarray analysis, a hierarchical clustering analysis of the data has been carried out [35]. As a crucial quality control assessment, we are very pleased with our analysis in which replicates of each type of resistant lines do cluster together.…”