Epigenetic mechanisms in breast cancer therapy and resistance

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Abstract

The majority of breast cancers express the estrogen receptor (ERα) and agents targeting this pathway represent the main treatment modality. Endocrine therapy has proven successful in the treatment of hormone-responsive breast cancer since its early adoption in the 1940s as an ablative therapy. Unfortunately, therapeutic resistance arises, leading to disease recurrence and relapse. Recent studies increased our understanding in how changes to the chromatin landscape and deregulation of epigenetic factors orchestrate the resistant phenotype. Here, we will discuss how the epigenome is an integral determinant in hormone therapy response and why epigenetic factors are promising targets for overcoming clinical resistance.

Abstract

Endocrine therapy has been the mainstay for hormone responsive breast cancer treatment. Here, Garcia-Martinez and colleagues discuss epigenetic mechanisms regulating ER + breast cancer and endocrine therapy resistance, and highlight approaches to rewire the cancer epigenome to improve targeted therapies for this cancer.

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Most cited references 118

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Dynamic RNA Modifications in Gene Expression Regulation

Molly E Evans, Ian A Roundtree, Tao Pan … (2017)

Over 100 types of chemical modifications have been identified in cellular RNAs. While the 5' cap modification and the poly(A) tail of eukaryotic mRNA play key roles in regulation, internal modifications are gaining attention for their roles in mRNA metabolism. The most abundant internal mRNA modification is N6-methyladenosine (m6A), and identification of proteins that install, recognize, and remove this and other marks have revealed roles for mRNA modification in nearly every aspect of the mRNA life cycle, as well as in various cellular, developmental, and disease processes. Abundant noncoding RNAs such as tRNAs, rRNAs, and spliceosomal RNAs are also heavily modified and depend on the modifications for their biogenesis and function. Our understanding of the biological contributions of these different chemical modifications is beginning to take shape, but it's clear that in both coding and noncoding RNAs, dynamic modifications represent a new layer of control of genetic information.

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Reading, writing and erasing mRNA methylation

Sara Zaccara, Ryan Ries, Samie R. Jaffrey (2019)

RNA methylation to form N6-methyladenosine (m6A) in mRNA accounts for the most abundant mRNA internal modification and has emerged as a widespread regulatory mechanism that controls gene expression in diverse physiological processes. Transcriptome-wide m6A mapping has revealed the distribution and pattern of m6A in cellular RNAs, referred to as the epitranscriptome. These maps have revealed the specific mRNAs that are regulated by m6A, providing mechanistic links connecting m6A to cellular differentiation, cancer progression and other processes. The effects of m6A on mRNA are mediated by an expanding list of m6A readers and m6A writer-complex components, as well as potential erasers that currently have unclear relevance to m6A prevalence in the transcriptome. Here we review new and emerging methods to characterize and quantify the epitranscriptome, and we discuss new concepts - in some cases, controversies - regarding our understanding of the mechanisms and functions of m6A readers, writers and erasers.

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Palbociclib and Letrozole in Advanced Breast Cancer.

Richard Finn, Miguel Martín, Hope Rugo … (2016)

Background A phase 2 study showed that progression-free survival was longer with palbociclib plus letrozole than with letrozole alone in the initial treatment of postmenopausal women with estrogen-receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer. We performed a phase 3 study that was designed to confirm and expand the efficacy and safety data for palbociclib plus letrozole for this indication. Methods In this double-blind study, we randomly assigned, in a 2:1 ratio, 666 postmenopausal women with ER-positive, HER2-negative breast cancer, who had not had prior treatment for advanced disease, to receive palbociclib plus letrozole or placebo plus letrozole. The primary end point was progression-free survival, as assessed by the investigators; secondary end points were overall survival, objective response, clinical benefit response, patient-reported outcomes, pharmacokinetic effects, and safety. Results The median progression-free survival was 24.8 months (95% confidence interval [CI], 22.1 to not estimable) in the palbociclib-letrozole group, as compared with 14.5 months (95% CI, 12.9 to 17.1) in the placebo-letrozole group (hazard ratio for disease progression or death, 0.58; 95% CI, 0.46 to 0.72; P<0.001). The most common grade 3 or 4 adverse events were neutropenia (occurring in 66.4% of the patients in the palbociclib-letrozole group vs. 1.4% in the placebo-letrozole group), leukopenia (24.8% vs. 0%), anemia (5.4% vs. 1.8%), and fatigue (1.8% vs. 0.5%). Febrile neutropenia was reported in 1.8% of patients in the palbociclib-letrozole group and in none of the patients in the placebo-letrozole group. Permanent discontinuation of any study treatment as a result of adverse events occurred in 43 patients (9.7%) in the palbociclib-letrozole group and in 13 patients (5.9%) in the placebo-letrozole group. Conclusions Among patients with previously untreated ER-positive, HER2-negative advanced breast cancer, palbociclib combined with letrozole resulted in significantly longer progression-free survival than that with letrozole alone, although the rates of myelotoxic effects were higher with palbociclib-letrozole. (Funded by Pfizer; PALOMA-2 ClinicalTrials.gov number, NCT01740427 .).

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Author and article information

Contributors

Ho Lam Chan:

ORCID: http://orcid.org/0000-0001-9799-0618

candyhlchan@gmail.com

Lluis Morey:

ORCID: http://orcid.org/0000-0001-9851-4066

lmorey@med.miami.edu

Journal

Journal ID (nlm-ta): Nat Commun

Journal ID (iso-abbrev): Nat Commun

Title: Nature Communications

Publisher: Nature Publishing Group UK (London )

ISSN (Electronic): 2041-1723

Publication date (Electronic): 19 March 2021

Publication date PMC-release: 19 March 2021

Publication date Collection: 2021

Volume: 12

Electronic Location Identifier: 1786

Affiliations

[1 ]GRID grid.419791.3, ISNI 0000 0000 9902 6374, Sylvester Comprehensive Cancer Center, ; Miami, FL USA

[2 ]GRID grid.26790.3a, ISNI 0000 0004 1936 8606, Department of Human Genetics, , University of Miami Miller School of Medicine, Biomedical Research Building, ; Miami, FL USA

Author information

Liliana Garcia-Martinez http://orcid.org/0000-0002-3015-5543

Ho Lam Chan http://orcid.org/0000-0001-9799-0618

Lluis Morey http://orcid.org/0000-0001-9851-4066

Article

Publisher ID: 22024

DOI: 10.1038/s41467-021-22024-3

PMC ID: 7979820

PubMed ID: 33741974

SO-VID: 7e3a6f71-0440-4fbe-9320-7940909e0dd8

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 9 July 2020

Date accepted : 22 February 2021

Funding

Funded by: FundRef https://doi.org/10.13039/100006827, Florida Department of Health;

Award ID: 20B15

Award Recipient : Lluis Morey

Funded by: FundRef https://doi.org/10.13039/100001368, V Foundation for Cancer Research (V Foundation);

Funded by: FundRef https://doi.org/10.13039/100005189, Leukemia and Lymphoma Society (Leukemia & Lymphoma Society);

Funded by: Lampert Breast Cancer Research Fund

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ScienceOpen disciplines: Uncategorized

Keywords: breast cancer,endocrine system and metabolic diseases

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ScienceOpen disciplines: Uncategorized

Keywords: breast cancer, endocrine system and metabolic diseases

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Epigenetic mechanisms in breast cancer therapy and resistance

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Karger: Oncology

Most cited references 118

Dynamic RNA Modifications in Gene Expression Regulation

Reading, writing and erasing mRNA methylation

Palbociclib and Letrozole in Advanced Breast Cancer.

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