Predicting resistance to endocrine therapy in breast cancer: It's time for epigenetic biomarkers (Review)
- Authors:
- Published online on: January 11, 2019 https://doi.org/10.3892/or.2019.6967
- Pages: 1431-1438
Abstract
Introduction
Most breast cancers (BC), over 2/3 of cases, express estrogen (ER) and progesterone (PR) receptors (1). This is extremely important since these are used as biomarkers for subtype classification, with implications in choice of treatment and prognosis in BC patients (2). Notably, endocrine therapies (ET) have been successfully used for treating ER positive BC patients with significant impact in patient outcome. Several endocrine drugs are approved for BC treatment, most notably tamoxifen, toremifene, anastrozole, letrozole, exemestane and fulvestrant, which may be used in different clinical contexts, such as chemoprophylaxis, neoadjuvant, adjuvant and palliative treatments. However, the effectiveness of ET is limited as up to 40% of patients may experience disease recurrence while on ET adjuvant treatment (1,3). Moreover, in the metastatic setting, acquired resistance to ET is virtually an universal feature, and is clinically defined in accordance to the 3rd ESO-ESMO International Consensus Guidelines (4) and many efforts have been made to understand the mechanisms involved in acquisition of acquired resistance to ET. These, however, remain mostly elusive and no biomarkers have been validated in this setting despite intense drug development and approval.
Epigenetics may be defined as mechanisms that regulate cell fate specifications, while the DNA remains unchanged (5). Some of these mechanisms include DNA methylation, non-coding RNAs, chromatin remodeling and histone post-translational modifications or variants. Collectively, these components constitute the epigenome machinery whose role is to define which information is available for transcription and for translation (5). DNA methylation is performed by specific enzymes, the DNA methyltransferases (DNMTs) that introduce a methyl group at the 5′ position of a cytosine ring inside CpG dinucleotides (6). Globally, promoter methylation of genes is associated with transcription inhibition (6). Furthermore, the N-terminal tails of histones may undergo post-translation modifications that subsequently impact the chromatin structure (7). The most well-studied histone post-translation modifications are histone acetylation and histone methylation. Histone acetylation is associated with gene expression and is carried out by histone acetyltransferases (HATs), while histone deacetylation is accomplished by histone deacetylases (HDACs) (7). Histone methylation, which depending on the residue and the number of methyl groups may lead either to transcription repression or activation (8), is catalyzed by histone methyltransferases (HMTs), while histone demethylation is performed by histone demethylases (HDMs) (7). In addition to post-translational histone modifications, histone variants that can replace canonical histones are an additional level of epigenetic complexity, and contribute to the shaping of the chromatin structure.
Non-coding RNAs (ncRNAs) comprise a hidden layer of internal signals that control various levels of gene expression (9). Among these, microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) are the most frequently reported in BC. lncRNAs are ncRNA molecules usually longer than 200 nucleotides that do not fit into known classes of small or structural RNAs (9) and may act as protein-DNA or protein-protein scaffolds, miRNA sponges, protein decoys, or regulators of translation (10). miRNAs are endogenous, small non-coding single-stranded RNAs with ~22 nucleotides in length, that exert a finely tuned regulation of gene expression at the post-transcriptional level (11) by binding to mRNA targets, inducing its cleavage or repressing its translation (11).
Over the last few years, convincing data has suggested that altered epigenetic regulation may be involved in tumor initiation, progression and cancer resistance to therapy, including endocrine resistance, particularly in BC. For instance, ER expression is currently one of the foremost predictive biomarkers of response to ET, and altered expression of ER may be due to hypermethylation of CpG islands within its promoter, increased histone deacetylase activity in the ESR1 promoter or translational repression by miRNAs (12). Since ER was found to be deleted in only 15–20% of endocrine-resistant BC, several epigenetic mechanisms may be involved in the development of endocrine treatment-resistance (3), and some of these are depicted in Fig. 1.
Our objective was to review the published evidence regarding epigenetic mechanisms associated to ET resistance in BC, as it may be considered an emerging subject and worth special focus.
Evidence acquisition
For the selection of the most relevant bibliography, we conducted a PubMed® search using the terms ‘endocrine resistance’, ‘breast cancer’ and ‘epigenetic mechanisms’. Reference lists from key articles were also searched for additional relevant data. The criteria for article selection were: written in English, central theme based on ET resistance on BC and epigenetic mechanisms. Original studies were selected based on the detail of analysis, mechanistic support of data, novelty, and potential clinical usefulness of the findings. Chemotherapy/radiotherapy-resistance, HER2-enriched subtype or ‘triple negative’ BC citations were excluded for being outside the scope of this review.
DNA methylation
DNA methylation is one of the most common epigenetic changes and has been reported in multiple tumors, including BC (9,13). This epigenetic alteration is inherently stable and has been proposed as a promising cancer biomarker in multiple cancers since it can be sampled from less invasive sources such as liquid biopsies (plasma or urine) (13–15). Thus, the role of DNA methylation as a predictor of ET resistance is a field of growing interest and has become the focus of several research teams (16–18) since it may improve BC patients' risk stratification.
Notably, Stone et al reported that in endocrine treated-resistant cell lines, DNA hypermethylation occurs predominantly at estrogen-responsive enhancers, leading to reduced ER binding and subsequently to expression downregulation. Furthermore, luminal subtype BC patients with relapsed disease exhibited significantly higher methylation levels at all enhancer loci studied (19). By comparing anti-estrogen-resistant cell lines with the parental sensitive cell line, DNA methylation of the promoter region of genes was also suggested to play a role in the emergence of endocrine resistance (17,20) (Table I). Multicenter studies, including several cohorts of BC patients were able to confirm these findings. Specifically, PITX2 methylation levels were consistently identified as a valuable biomarker to predict outcome in low-risk BC patients (ER-positive, node-negative) treated with surgery followed by adjuvant tamoxifen (21,22). Nevertheless, multiple validations are still required before the implementation of these markers in the clinical setting (Table I). Thus, to date, no clinical trials have assessed the clinical relevance of these candidate biomarkers.
 | Table I.DNA methylation of the promoter region of genes as predictive biomarkers to different modalities of endocrine therapies along with their role and the biological samples used in each study. |
Non-coding RNAs
As previously mentioned, decreased ER expression may be due to post-transcription regulation of miRNAs, including that of miR-221/222, whose overexpression has been associated with resistance to tamoxifen (23,24) and fulvestrant (25). Conversely, miR-342-3p levels were revealed to be positively correlated with ER mRNA expression in human BC and associated with tamoxifen sensitivity (26,27). miRNAs that regulate growth, survival, apoptosis, epithelial-mesenchymal transition (EMT) and metastasis of BC cells may be implicated in loss of responsiveness to ET. In particular, PTEN downregulation due to specific miRNAs, permitting abnormal Pi3K/Akt pathway activation, promote estrogen-independent growth and survival of BC cells leading to endocrine treatment resistance (28,29).
Several clinical trials are currently ongoing to evaluate the role of miRNAs as predictive biomarkers in BC. Specifically, trials such as NCT01231386 and NCT01722851, aim to identify circulating miRNAs aiding at the identification of biomarkers of early response to neoadjuvant therapy, including ET, which may be used as potential targets for personalized therapies. Conversely, the NCT01612871 trial was set to explore a panel of circulating miRNAs that could aid to monitor the disease status of the patient while on adjuvant ET (30–32).
lncRNAs have also been associated with endocrine treatment resistance. Particularly, lncRNAs, breast cancer anti-estrogen resistance 4 (BRCAAR4) overexpression (33,34) and DSCAM antisense RNA 1 (DSCAM-AS1) (35), which contains an ER promoter binding motif, have been revealed to predict tamoxifen resistance in primary BC (Table II and Fig. 1).
| Table II.Non-coding RNAs involved in response (sensitivity/resistance) to different modalities of endocrine therapies along with their putative targets/mechanism and the biological samples used in each study. |
Chromatin remodeling, post-translational histone modifications and histone variants
Histone post-translation modifications induce chromatin landscape changes that subsequently favor ER repression, thus promoting other signaling pathways that could lead to endocrine resistance, as exemplified by Magnani et al that revealed how the genome's accessibility is altered in drug-resistant vs. drug-responsive BC cells (36). Recently, expression of the H3K36 methyltransferase NSD2 was found to be higher in tamoxifen-resistant BC cell lines, associated with disease recurrence and worse survival (37). Furthermore, H3K37me3 profiles enabled the identification of patients with poor outcome after aromatase inhibitor (AI) treatment (38).
Furthermore, it was recently demonstrated that transcription repression performed by ER co-repressors confer tamoxifen sensitivity through recruitment of HDACs to DNA (39). This evidence suggests that loss of ER co-repressors may sensitize BC cells to the cytotoxic effects of HDACs inhibitors (HDACi). Notably, some clinical trials have demonstrated that HDACi appears to re-establish sensitivity to anti-estrogens in a subset of endocrine treated-resistant tumors (40,41). In addition, the ENCORE-301, a randomized phase II trial (41) tested entinostat, an oral HDACi, in the endocrine-resistance, more specifically AI in post-menopausal women. The results revealed modest improvement in PFS but much greater improvement in overall survival (OS)-median OS improved to 28.1 months in the experimental arm vs. 19.8 months (HR, 0.59; 95% CI, 0.36 to 0.97; P=0.036). Ongoing clinical trials are further testing entinostat in monotherapy or in combination. Moreover, in custom-generated tamoxifen resistant cell lines, treatment with HDACi re-established sensitivity to tamoxifen through significant Bcl-2 downregulation, growth arrest and apoptosis (42).
Histone variants, such as H2A.Z, an H2A variant, have been shown to be intimately linked to estrogen signaling (43). Notably, a study has already provided a link (yet uncharacterized) between H2A.Z and endocrine resistance by revealing that H2A.Z overexpression led to increased estrogen-independent proliferation (44). Furthermore, another study demonstrated that the histone HIST1H2BE, an H2B variant, was overexpressed not only in endocrine-resistant cell lines, but also in AI-treated tumors from patients which relapsed compared to those that did not (45).
Furthermore, an emerging class of transcription factors named ‘pioneer factors’, appear to be key players in shaping chromatin structure through binding to chromatin prior to transcription factors, making it accessible for transcription factors, together with histone post-translation modifications and histone variants [68–70]. PBX1 is an example of this class-its expression levels have been associated with reduced metastasis-free survival in ER-positive BC patients (46). Furthermore, a gene expression signature based on NOTCH-PBX1 activity was found to discriminate BC patients that are responsive to ET from those which are not. Notably, PBX1 knockdown was sufficient to arrest ER-resistant BC cell growth (36).
These and other chromatin remodeling complexes associated with endocrine resistance are summarized in Table III along with their putative role and the biological samples in which they were characterized.
| Table III.Chromatin remodeling, post-translational histone modifications and histone variants involved in response (sensitivity/resistance) to endocrine therapies along with their putative epigenetic mechanism and role in response. |
Conclusion
Notwithstanding the prevalence of endocrine treatment resistance in BC, predictive and diagnostic biomarkers in this setting are markedly lacking in clinical practice. In this review, we summarized emerging evidence that epigenetic mechanisms may prove useful for this purpose. These would perform as non-invasive predictive biomarkers of treatment-resistance, providing affordable and sequential monitoring during the course of treatment. The concept of early detection (preclinical) of therapy resistance is compelling, as it could assist clinicians in choosing the most appropriate individualized therapeutic strategy.
Furthermore, some epigenetic modifications in addition to conveying information concerning prediction of response, are also appealingly targetable, in particular due to their reversible nature. The clinical usefulness of these findings, however, is still elusive, mostly due to lack of standardization in methodology, limiting reproducibility.
Promising results have been arising in clinically meaningful trials, such as ENCORE-301. A useful approach would be the integration of the candidate biomarkers into a panel, enabling its validation in a clinical trial setting. Hopefully, this will be accomplished in the near future.
Acknowledgments
Not applicable.
Funding
The present study was supported by a grant from the Research Center of Portuguese Oncology Institute of Porto (PI 74-CI-IPOP-19-2016) and the Portuguese Society of Oncology-YOuR Project. SS was supported by a PhD fellowship IPO/ESTIMA-1 NORTE-01-0145-FEDER-000027.
Availability of data and materials
The datasets used during the present study are available from the corresponding author upon reasonable request.
Authors' contributions
MFS, SPDS, RH and CJ conceived and designed the review. MFS, MA, SS performed the literature search and wrote the manuscript. SPDS, RH and CJ reviewed and edited the manuscript. All authors read and approved the manuscript and agree to be accountable for all aspects of the research in ensuring that the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
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