Abstract
Endocrine therapy is the mainstay of treatment in estrogen receptor-positive breast cancers and significantly reduces disease recurrence and breast cancer-related mortality. However, acquired resistance to therapy has been noted in nearly one-third of women treated with tamoxifen and other endocrine therapies. Mutations in the estrogen receptor have long been speculated to play a role in endocrine therapy resistance but have been rarely detected. However, recent studies utilizing next-generation sequencing on estrogen receptor-positive, metastatic clinical samples have revealed that recurrent ESR1 mutations are far more frequent than previously thought and may play an important role in acquired endocrine therapy resistance. Here we review recent advances in detection and characterization of ESR1 mutations in advanced, endocrine therapy-resistant breast cancers.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-014-0494-7) contains supplementary material, which is available to authorized users.
Highlights
Acquired resistance to drug treatment is a major problem in cancer therapy
Several strategies for inhibiting the estrogen axis in breast cancer exist, including: selective estrogen receptor (ER) modulators such as tamoxifen and raloxifene, which act as selective tissue-specific antagonists of ER in the breast [9]; selective ER degraders such as fulvestrant, which promote ER turnover [10]; and aromatase inhibitors such as exemestane, anastazole and letrazole – agents primarily used in postmenopausal women with ER-positive breast cancer – which inhibit estrogen biosynthesis [11]
In summary, ESR1 mutations are significantly enriched in endocrine therapy-resistant, metastatic breast cancer and are rare or nonexistent in treatment-naïve, primary tumors (Figure 1)
Summary
Acquired resistance to drug treatment is a major problem in cancer therapy. While many mechanisms of drug resistance to chemotherapeutic agents such as efflux, metabolism and inactivation have been described previously, alterations within the drug target have emerged as a dominant resistance mechanism to targeted therapies [1]. Our findings of acquired ESR1 mutations in metastatic, endocrine therapy-resistant breast cancers have been independently corroborated by other groups and have been described previously by Li and colleagues in ER-positive xenografts derived from poor-prognosis, treatment-resistant tumors [27]. In another study that included 13 tumor samples from Israeli patients with metastatic, ER-positive breast cancer who failed multiple treatments, Merenbakh-Lamin and coworkers performed commercially available genetic analysis by next-generation sequencing of 182 cancerrelated genes on DNA extracted from formalin-fixed paraffin-embedded tissue samples and reported ER D538G mutation in five patients (38%) [31]. The mutant Y537S apostructure showed a high degree of similarity to wild-type ER bound to diethylstilbesterol [35], a full ER agonist, confirming that the Y537S mutant mimics the ligandoccupied, active ER conformation These studies have shown that Tyr537 hydrogen bonds with Asn348 in the wild-type receptor, resulting in stabilization of the backbone of the helix 11–12 loop and leaving Leu536 in a solvent-exposed position. The structural basis for constitutive activity of other mutant ER proteins is less well understood biochemical characterization of some of these mutant proteins has been described [36,37,38,39]
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