Abstract
The incidence of breast cancer (BC) worldwide is on the rise due to reasons such as late detection, limited treatment choices for certain BC subtypes, and the development of drug resistance. These factors combined lead to unfavorable clinical results. Recent studies highlight the crucial significance of epigenetic changes in the development of BC, especially in relation to medication resistance and the preservation of stemness traits. Continuing research in the field of epigenetics and breast cancer carcinogenesis is crucial for overcoming present challenges and advancing our knowledge in this area, ultimately resulting in better outcomes for patients.
Main Text
Breast cancer accounts for approximately 6.6% of cancer deaths worldwide [1]. It is one of the most common malignancies in women. Breast cancer is a heterogeneous disease and consists of several subtypes. The main cause of Breast cancer has been recognized due to mutations in crucial genes like BRCA1 and BRCA2 [2]. However, according to the literature over the past two decades, it has been predominantly shown that epigenetic modifications are mostly responsible for the advancement of breast cancer [3]. Epigenetic alterations contribute to the initiation and progression of breast cancer by affecting critical genes involved in cell growth, proliferation, and DNA repair [4]. Epigenetic alterations are now considered a major emphasis in breast cancer diagnosis and treatment and therapeutic investigation [5].
Recently, Prabhu and coworker [6] discussed the role of epigenetic modifications as potential sources for novel diagnostic markers, more precise prognostic indications, and the identification of trustworthy predictors of therapy response in breast malignancies [6]. The authors have thoroughly discussed the complex field of epigenetic modifications in cancer, investigating how they interact with genetic changes and their resulting effects on tumor heterogeneity and resistance to treatment. These areas are still not well understood and need clear explanations [7,8]. The study’s main objective is to clarify the existing knowledge on epigenetic modifications as catalysts of cancer variety and their contribution to promoting resistance against traditional treatments [9]. Prabhu and colleagues [6] further highlight the complex nature of epigenetic changes in cancer. Study further analyzes the impact of these alterations on the underlying biology of cancer cells, which may result in diverse reactions to treatment. These innovative methods provide a hopeful solution to combat medication resistance, a widespread obstacle in cancer therapy. Furthermore, the intricacies and difficulties encountered in transforming these epigenetic findings from the bench to bedside are a crucial stage in actualizing their medicinal capabilities [10,11]. The objective of this publication is to stimulate additional study in this swiftly developing topic. The goal is to enhance cancer management options by examining the complex relationship involving epigenetic and genetic alterations in cancer. The ultimate objective is to have a beneficial influence on the survival rate of cancer patients globally by establishing the groundwork for efficient and tailored therapeutical approaches.
In recent years, the domain of epigenetics has advanced considerably, uncovering an intricate relationship between gene expression and environmental influences. Although conventional discourse typically emphasizes established mechanisms like DNA methylation [12], histone modification [13], acetylation [14] and non-coding RNAs [15], it is essential to explore emerging ideas that underscore the dynamic character of these processes. Notwithstanding progress, significant gaps persist in our comprehension of the operational dynamics of these epigenetic systems in real-time and across many contexts. Although it is established that environmental stressors can induce epigenetic modifications, the specific mechanisms and enduring consequences of these changes remain inadequately clarified. This offers researchers the chance to investigate how epigenetic alterations affect health outcomes, especially with chronic diseases and mental health disorders.
Epigenetics was first defined by Conrad Waddington in early 1940 as "the branch of biology which studies the causal interactions between genes and their products which bring the phenotype into being" [16]. Epigenetics are very complex mechanisms to control the patterns of gene expression in response to diverse environmental stimuli and developmental signals [17]. The negatively charged DNA is wrapped around a positively charged histone protein octamer with two copies of H2A, H2B, H3, and H4 [18]. Understanding epigenetic processes is crucial for deciphering the molecular basis of diseases and potentially developing new therapeutic approaches.
There is growing interest in the use of epigenetic modifications in medical sciences [19]. Interestingly, due to their stability, frequency, reversibility, and accessibility in body fluids, epigenetic changes are novel cancer biomarkers with significant assay development potential to help with patient treatment [20]. Epigenetics modification has many promising diagnostic applications; (a) Epigenetic Biomarkers: Epigenetic alterations can serve as biomarkers for breast cancer diagnosis and prognosis. DNA methylation patterns of specific genes have been identified as potential diagnostic biomarkers in breast cancer. Detecting these methylation patterns in body fluids or tissue samples could aid in early detection and more accurate disease stratification. (b) Liquid Biopsies: Liquid biopsies involve analyzing circulating tumor cells (CTCs) or cell-free DNA (cfDNA) in the blood. Epigenetic modifications in CTCs or cfDNA can provide information about the tumor's molecular characteristics and its response to treatment. Liquid biopsies may offer a less invasive and more dynamic approach for monitoring treatment response and disease progression, (c) Predicting Treatment Response: Epigenetic profiling of tumors could help predict how a patient will respond to specific therapies. Identifying certain epigenetic patterns could guide clinicians in selecting the most effective treatment options for individual patients, leading to personalized medicine approaches.
In addition to diagnostic applications, epigenetics has also many therapeutic applications including (a) Epigenetic Targeted Therapies: Drugs that target epigenetic regulators, such as DNA methyltransferases (DNMTs) and histone deacetylases (HDACs), are being developed as potential therapeutic options for breast cancer [21,22]. These drugs aim to reverse aberrant epigenetic changes, reactivating tumor suppressor genes and blocking oncogenes. (b) Combination Therapies: Epigenetic drugs are often used in combination with chemotherapy or targeted therapies to improve treatment success. These drugs improve patient outcomes by sensitizing tumor cells to other anticancer treatments by modifying the epigenetic landscape. (c) Epigenetic Immunotherapy: Epigenetic modifications in the tumor microenvironment can influence the immune response. Epigenetic immunotherapy aims to enhance the antitumor immune response by targeting immune-related genes through epigenetic modulation.
In conclusion, epigenetic alterations in breast cancer have opened new avenues for diagnosis and treatment. Utilizing epigenetic biomarkers and developing targeted epigenetic therapies may lead to more effective and personalized approaches for managing breast cancer in the future. However, further research and clinical studies are essential to fully realize the potential of epigenetic-based diagnostic and therapeutic applications.
References
2. Liu M, Xie F, Liu M, Zhang Y, Wang S. Association between BRCA mutational status and survival in patients with breast cancer: A systematic review and meta-analysis. Breast Cancer Research and Treatment. 2021 Apr;186:591-605.
3. Shukla S, Penta D, Mondal P, Meeran SM. Epigenetics of breast cancer: clinical status of epi-drugs and phytochemicals. Breast cancer metastasis and Drug Resistance: Challenges and Progress. 2019;1152:293-310.
4. Sher G, Salman NA, Khan AQ, Prabhu KS, Raza A, Kulinski M, et al. Epigenetic and breast cancer therapy: promising diagnostic and therapeutic applications. Semin Cancer Biol, 2022 Aug ; 83: 152-165.
5. Yu X, Zhao H, Wang R, Chen Y, Ouyang X, Li W, et al. Cancer epigenetics: from laboratory studies and clinical trials to precision medicine. Cell Death Discovery. 2024 Jan 15;10(1):28.
6. Prabhu KS, Sadida HQ, Kuttikrishnan S, Junejo K, Bhat AA, Uddin S. Beyond genetics: Exploring the role of epigenetic alterations in breast cancer. Pathology-Research and Practice. 2024 Jan 26:155174.
7. Haven B, Heilig E, Donham C, Settles M, Vasilevsky N, Owen K, Reproducibility Project: Cancer Biology. Registered report: A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations. Elife. 2016 Feb 23;5:69-80.
8. Esteller M. Epigenetics in cancer. New England Journal of Medicine. 2008 Mar 13;358(11):1148-59.
9. Terranova-Barberio M, Thomas S, Munster PN. Epigenetic modifiers in immunotherapy: a focus on checkpoint inhibitors. Immunotherapy. 2016 Jun;8(6):705-19.
10. Sadida HQ, Abdulla A, Al Marzooqi S, Hashem S, Macha MA, Akil AS, et al. Epigenetic modifications: Key players in cancer heterogeneity and drug resistance. Translational Oncology. 2024 Jan 1;39:101821.
11. Chi Y, Wang D, Wang J, Yu W, Yang J. Long non-coding RNA in the pathogenesis of cancers. Cells. 2019 Sep 1;8(9):1015.
12. Moore LD, Le T, Fan G. DNA methylation and its basic function. Neuropsychopharmacology. 2013 Jan;38(1):23-38.
13. Stamidis N, Żylicz JJ. RNA‐mediated heterochromatin formation at repetitive elements in mammals. The EMBO Journal. 2023 Apr 17;42(8):e111717.
14. Bowman GD, Poirier MG. Post-translational modifications of histones that influence nucleosome dynamics. Chemical Reviews. 2014 Nov 26;115(6):2274-95.
15. Mattick JS, Amaral PP, Carninci P, Carpenter S, Chang HY, Chen LL, et al. Long non-coding RNAs: definitions, functions, challenges and recommendations. Nature reviews Molecular Cell Biology. 2023 Jun;24(6):430-47.
16. Tronick E, Hunter RG. Waddington, dynamic systems, and epigenetics. Frontiers in Behavioral Neuroscience. 2016 Jun 10;10:107.
17. Moore PC, Henderson KW, Classon M. The epigenome and the many facets of cancer drug tolerance. Adv Cancer Res. 2023;158:1-39.
18. Quina, A.S., M. Buschbeck, and L. Di Croce, Chromatin structure and epigenetics. Biochem Pharmacol, 2006. 72(11): p. 1563-9.
19. Gerra MC, Dallabona C, Cecchi R. Epigenetic analyses in forensic medicine: future and challenges. International Journal of Legal Medicine. 2024 May;138(3):701-19.
20. Gao J, Shi W, Wang J, Guan C, Dong Q, Sheng J, et al. Research progress and applications of epigenetic biomarkers in cancer. Frontiers in Pharmacology. 2024 Apr 12;15:1308309.
21. Zhuang J, Huo Q, Yang F, Xie N. Perspectives on the role of histone modification in breast cancer progression and the advanced technological tools to study epigenetic determinants of metastasis. Frontiers in Genetics. 2020 Oct 29;11:603552.
22. Abdelaziz N, Therachiyil L, Sadida HQ, Ali AM, Khan OS, Singh M, Khan AQ, Akil AS, Bhat AA, Uddin S. Epigenetic inhibitors and their role in cancer therapy. InInternational Review of Cell and Molecular Biology 2023 Jan; 380:211-51.