New experimental models for aromatase inhibitor resistance

Abstract

Clinical trials have demonstrated the importance of aromatase inhibitor (AI) therapy in the effective treatment of hormone-dependent breast cancers. In contrast to tamoxifen, an antagonist of the estrogen receptor (ER), AIs have shown to be better tolerated along with decreased recurrence rates of the disease. Currently, three third-generation AIs are being used: exemestane, letrozole and anastrozole. Our laboratory is attempting to understand several aspects of aromatase inhibitor functionality. In this paper, we first review recent findings from our structure-function studies of aromatase as well as the molecular characterization of the interaction between AIs and aromatase. Based on these studies, we propose new evidence for the interaction of letrozole and exemestane with aromatase. In addition, we will discuss recent results generated from our AI-resistant cell lines. Our laboratory has generated MCF-7aro cells that are resistant to letrozole, anastrozole, exemestane and tamoxifen. Basic functional characterization of aromatase and ERα in these resistant cell lines has been done and microarray analysis has been employed in order to better understand the mechanism responsible for AI resistance on a genome-wide scale. The results generated so far suggest the presence of at least four types of resistant cell lines. Overall, the information presented in this paper supplements our understanding of AI function, and such information can be valuable for the development of treatment strategies against AI resistant breast cancers.

Increased estrogen sulfatase (STS) and 17β-hydroxysteroid dehydrogenase type 1(17β-HSD1) following neoadjuvant aromatase inhibitor therapy in breast cancer patients

“…Approximately 60% of premenopausal and 75% of postmenopausal patients have sex steroid hormone-dependent breast carcinoma [3,4]. Among these sex steroids, estrogens, especially estradiol or E2, a biologically potent estrogen, play pivotal roles in cell proliferation, development, and invasion of these hormonedependent breast carcinoma cells [3][4][5].…”

The Role of Amphiregulin in Exemestane-Resistant Breast Cancer Cells: Evidence of an Autocrine Loop

“…These resistant cell lines were selected under the following conditions: testosterone plus letrozole (T + LetR), testosterone plus anastrozole (T + AnaR), anastrozole only (AnaR), testosterone plus exemestane (T + ExeR), exemestane only (ExeR), or long-term estrogen deprivation (LTEDaro). MCF-7aro cells cultured in testosterone (in which testosterone was converted to 17h-estradiol) were used as positive controls (2,3).…”

Bicyclic Substituted Hydroxyphenylmethanone Type Inhibitors of 17 β‐Hydroxysteroid Dehydrogenase Type 1 (17 β‐HSD1): The Role of the Bicyclic Moiety

“…Accordingly, introduction of substituents into the benzyloxy moiety might lead to further enhancement of selectivity. While this hypothesis was confirmed by the meta-methoxy (13), dimethoxy (16) and the chloro derivatives (17)(18)(19), the monomethoxy compounds (14)(15) showed different results. Compounds 14 (meta-methoxy, SF = 16) and 15 (para-methoxy, SF = 12) revealed similar selectivity toward 17b-HSD2 as the nonsubstituted benzyloxy compound 12 (SF = 13).…”

“…Regarding the benzyloxy-substituted compounds 12-19, only the monomethoxy-substituted benzyloxy derivatives 13-15 showed moderate inhibition of E2 formation (IC 50 = 526, 441 and 565 nm, respectively). However, the dimethoxy (16) and chloro substituents (17)(18)(19) have a negative impact on cellular activity, which might be explained by insufficient cell penetration or increased intracellular metabolism. Interestingly, the ethoxy derivative 10, without an additional phenyl ring, exhibited a three-to fourfold higher intracellular inhibitory activity (IC 50 = 154 nm) than compounds 13-15.…”