Epigenetics in Breast Cancer Therapy—New Strategies and Future Nanomedicine Perspectives

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Despite advances in cancer treatment, difficult-to-treat tumor subtypes remain a challenge. New multidisciplinary approaches can help overcome current obstacles posed by tumor heterogeneity, activation and enrichment of cancer stem cells, and acquired drug resistance development. Epigenome modulation, currently unsuccessful in solid tumors due to epigenetic drug instability, toxicity, and off-target effects, might be enabled by implementing nano-based delivery strategies aiming to improve breast cancer patient outcomes.

Abstract

Epigenetic dysregulation has been recognized as a critical factor contributing to the development of resistance against standard chemotherapy and to breast cancer progression via epithelial-to-mesenchymal transition. Although the efficacy of the first-generation epigenetic drugs (epi-drugs) in solid tumor management has been disappointing, there is an increasing body of evidence showing that epigenome modulation, in synergy with other therapeutic approaches, could play an important role in cancer treatment, reversing acquired therapy resistance. However, the epigenetic therapy of solid malignancies is not straightforward. The emergence of nanotechnologies applied to medicine has brought new opportunities to advance the targeted delivery of epi-drugs while improving their stability and solubility, and minimizing off-target effects. Furthermore, the omics technologies, as powerful molecular epidemiology screening tools, enable new diagnostic and prognostic epigenetic biomarker identification, allowing for patient stratification and tailored management. In combination with new-generation epi-drugs, nanomedicine can help to overcome low therapeutic efficacy in treatment-resistant tumors. This review provides an overview of ongoing clinical trials focusing on combination therapies employing epi-drugs for breast cancer treatment and summarizes the latest nano-based targeted delivery approaches for epi-drugs. Moreover, it highlights the current limitations and obstacles associated with applying these experimental strategies in the clinics.

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Global Cancer Statistics 2018: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries

Ahmedin Jemal, Lindsey A Torre, Rebecca Siegel … (2018)

This article provides a status report on the global burden of cancer worldwide using the GLOBOCAN 2018 estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer, with a focus on geographic variability across 20 world regions. There will be an estimated 18.1 million new cancer cases (17.0 million excluding nonmelanoma skin cancer) and 9.6 million cancer deaths (9.5 million excluding nonmelanoma skin cancer) in 2018. In both sexes combined, lung cancer is the most commonly diagnosed cancer (11.6% of the total cases) and the leading cause of cancer death (18.4% of the total cancer deaths), closely followed by female breast cancer (11.6%), prostate cancer (7.1%), and colorectal cancer (6.1%) for incidence and colorectal cancer (9.2%), stomach cancer (8.2%), and liver cancer (8.2%) for mortality. Lung cancer is the most frequent cancer and the leading cause of cancer death among males, followed by prostate and colorectal cancer (for incidence) and liver and stomach cancer (for mortality). Among females, breast cancer is the most commonly diagnosed cancer and the leading cause of cancer death, followed by colorectal and lung cancer (for incidence), and vice versa (for mortality); cervical cancer ranks fourth for both incidence and mortality. The most frequently diagnosed cancer and the leading cause of cancer death, however, substantially vary across countries and within each country depending on the degree of economic development and associated social and life style factors. It is noteworthy that high-quality cancer registry data, the basis for planning and implementing evidence-based cancer control programs, are not available in most low- and middle-income countries. The Global Initiative for Cancer Registry Development is an international partnership that supports better estimation, as well as the collection and use of local data, to prioritize and evaluate national cancer control efforts. CA: A Cancer Journal for Clinicians 2018;0:1-31. © 2018 American Cancer Society.

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Molecular portraits of human breast tumours.

Charles Perou, Therese Sørlie, Michael B. Eisen … (2001)

Human breast tumours are diverse in their natural history and in their responsiveness to treatments. Variation in transcriptional programs accounts for much of the biological diversity of human cells and tumours. In each cell, signal transduction and regulatory systems transduce information from the cell's identity to its environmental status, thereby controlling the level of expression of every gene in the genome. Here we have characterized variation in gene expression patterns in a set of 65 surgical specimens of human breast tumours from 42 different individuals, using complementary DNA microarrays representing 8,102 human genes. These patterns provided a distinctive molecular portrait of each tumour. Twenty of the tumours were sampled twice, before and after a 16-week course of doxorubicin chemotherapy, and two tumours were paired with a lymph node metastasis from the same patient. Gene expression patterns in two tumour samples from the same individual were almost always more similar to each other than either was to any other sample. Sets of co-expressed genes were identified for which variation in messenger RNA levels could be related to specific features of physiological variation. The tumours could be classified into subtypes distinguished by pervasive differences in their gene expression patterns.

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The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups

Christina Curtis, Sohrab Shah, Suet-Feung Chin … (2012)

The elucidation of breast cancer subgroups and their molecular drivers requires integrated views of the genome and transcriptome from representative numbers of patients. We present an integrated analysis of copy number and gene expression in a discovery and validation set of 997 and 995 primary breast tumours, respectively, with long-term clinical follow-up. Inherited variants (copy number variants and single nucleotide polymorphisms) and acquired somatic copy number aberrations (CNAs) were associated with expression in ~40% of genes, with the landscape dominated by cis- and trans-acting CNAs. By delineating expression outlier genes driven in cis by CNAs, we identified putative cancer genes, including deletions in PPP2R2A, MTAP and MAP2K4. Unsupervised analysis of paired DNA–RNA profiles revealed novel subgroups with distinct clinical outcomes, which reproduced in the validation cohort. These include a high-risk, oestrogen-receptor-positive 11q13/14 cis-acting subgroup and a favourable prognosis subgroup devoid of CNAs. Trans-acting aberration hotspots were found to modulate subgroup-specific gene networks, including a TCR deletion-mediated adaptive immune response in the ‘CNA-devoid’ subgroup and a basal-specific chromosome 5 deletion-associated mitotic network. Our results provide a novel molecular stratification of the breast cancer population, derived from the impact of somatic CNAs on the transcriptome.

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Author and article information

Journal

Journal ID (nlm-ta): Cancers (Basel)

Journal ID (iso-abbrev): Cancers (Basel)

Journal ID (publisher-id): cancers

Title: Cancers

Publisher: MDPI

ISSN (Electronic): 2072-6694

Publication date (Electronic): 03 December 2020

Publication date Collection: December 2020

Volume: 12

Issue: 12

Electronic Location Identifier: 3622

Affiliations

[1 ]Cancer Research Institute, Biomedical Research Center of the Slovak Academy of Sciences, Dubravska Cesta 9, 845 05 Bratislava, Slovakia; verona.buocikova@ 123456savba.sk (V.B.); svetlana.miklikova@ 123456savba.sk (S.M.); alena.gabelova@ 123456savba.sk (A.G.)

[2 ]Department of Clinical Dentistry, University of Bergen, Aarstadveien 19, 5009 Bergen, Norway; ivan.rios-mondragon@ 123456uib.no (I.R.-M.); Mihaela.Cimpan@ 123456uib.no (M.R.C.)

[3 ]e-NIOS Applications Private Company, Alexandrou Pantou 25, 17671 Kallithea, Greece; epilalis@ 123456e-nios.com (E.P.); achatzi@ 123456e-nios.com (A.C.)

[4 ]Center of Systems Biology, Biomedical Research Foundation of the Academy of Athens, 11527 Athens, Greece

[5 ]2nd Department of Oncology, Faculty of Medicine, Comenius University and National Cancer Institute, Klenova 1, 833 10 Bratislava, Slovakia; michal.mego@ 123456nou.sk

[6 ]Latvian Institute of Organic Synthesis, Aizkraukles str. 21, LV-1006 Riga, Latvia; kpajuste@ 123456osi.lv (K.P.); rucins@ 123456osi.lv (M.R.); arkady@ 123456osi.lv (A.S.); aiva@ 123456osi.lv (A.P.)

[7 ]Health Effects Laboratory, NILU-Norwegian Institute for Air Research, 2007 Kjeller, Norway; ney@ 123456nilu.no (N.E.Y.); eml@ 123456nilu.no (E.M.L.); mdu@ 123456nilu.no (M.D.)

[8 ]Vall d Hebron, Institut de Recerca (VHIR), 08035 Barcelona, Spain; muriel.freixanet@ 123456vhir.org (M.F.); victor.puntes@ 123456vhir.org (V.P.)

[9 ]Institut Català de Nanosciència i Nanotecnologia (ICN2), Bellaterra, 08193 Barcelona, Spain

[10 ]Institució Catalana de Recerca i Estudis Avançats (ICREA), 08010 Barcelona, Spain

Author notes

[* ]Correspondence: bozena.smolkova@ 123456savba.sk

[†]

Alena Gabelova and Bozena Smolkova share the senior authorship.

Author information

Eleftherios Pilalis https://orcid.org/0000-0002-5253-5256

Aristotelis Chatziioannou https://orcid.org/0000-0003-2078-0844

Svetlana Miklikova https://orcid.org/0000-0003-0692-1858

Arkadij Sobolev https://orcid.org/0000-0002-5517-1240

Aiva Plotniece https://orcid.org/0000-0003-2187-5693

Maria Dusinska https://orcid.org/0000-0003-1358-1652

Alena Gabelova https://orcid.org/0000-0002-2674-2737

Bozena Smolkova https://orcid.org/0000-0002-4906-5652

Article

Publisher ID: cancers-12-03622

DOI: 10.3390/cancers12123622

PMC ID: 7761669

PubMed ID: 33287297

SO-VID: 1d04c385-03f6-4c02-b5d4-921c77098561

License:

Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

History

Date received : 31 October 2020

Date accepted : 30 November 2020

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Epigenetics in Breast Cancer Therapy—New Strategies and Future Nanomedicine Perspectives

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Abstract

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Karger: Oncology

Most cited references 250

Global Cancer Statistics 2018: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries

Molecular portraits of human breast tumours.

The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups

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Cited by 25

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