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 Table of Contents  
Year : 2018  |  Volume : 9  |  Issue : 4  |  Page : 155-164

Breast cancer stem cells, epigenetics, and radiation

1 Rutgers School of Graduate Studies; Department of Medicine, Hematology/Oncology, New Jersey Medical School, Rutgers School of Biomedical Health Science, São Paulo, Brazil
2 Rutgers School of Graduate Studies, New Jersey Medical School, São Paulo, Brazil
3 Department of Biochemistry, Institute of Chemistry, University of São Paulo, São Paulo, Brazil
4 Department of Pathology, Immunology and Laboratory Medicine, New Jersey Medical School, Rutgers School of Biomedical Health Science, Newark, NJ, USA
5 Department of Medicine, Hematology/Oncology, New Jersey Medical School, Rutgers School of Biomedical Health Science, Newark, NJ, USA

Date of Web Publication12-Mar-2019

Correspondence Address:
Dr. Pranela Rameshwar
Department of Medicine, Hematology/Oncology, New Jersey Medical School, Rutgers School of Biomedical Health Science, Newark, NJ
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jrcr.jrcr_29_18

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Breast cancer remains a clinical problem despite advancements in the field. Cancer stem cells (CSCs) within the breast cancer population are implicated in cancer relapse. The dormant CSCs generally resist available treatment, thus challenging the current treatment paradigm. Radiation is an aggressive form of treatment typically used to reduce tumor mass in breast cancer patients. Several clinical and research-based studies have shown that radiation treatment cannot target all cancer cells, leaving behind radioresistant cells. The radioresistant cells have the potential to acquire stem cell-like features that render them untargetable with respect to the current technology. This review elaborates on cancer cells acquiring stem cell phenotype. In addition, we discuss the phenotype and function of cancer cells that are derived from radioresistant cells as well as indirect changes as a consequence to bystander effect. In addition, the epigenetic profile of the radioresistant cells plays a crucial role in the acquisition of cycling quiescence and stem cell-like phenotype and is detailed in this review.

Keywords: Breast cancer, bystander, cancer stem cells, DNA methylation, epigenetics, epithelial to mesenchymal transition, histone modification, microRNA, radiation

How to cite this article:
Sinha G, Ferrer A, Naaldijk Y, Moore CA, Wu Q, Ulrich H, Rameshwar P. Breast cancer stem cells, epigenetics, and radiation. J Radiat Cancer Res 2018;9:155-64

How to cite this URL:
Sinha G, Ferrer A, Naaldijk Y, Moore CA, Wu Q, Ulrich H, Rameshwar P. Breast cancer stem cells, epigenetics, and radiation. J Radiat Cancer Res [serial online] 2018 [cited 2020 Jun 1];9:155-64. Available from: http://www.journalrcr.org/text.asp?2018/9/4/155/254002

  Introduction Top

Breast cancer

Breast cancer (BC) is the second leading cause of cancer following lung malignancy.[1] In 2017, approximately, 250,000 new cases were estimated in the United States.[2] As longevity increases, the number of BC-related deaths rises, exemplifying age as a critical factor in BC development.[1],[2],[3] Aside from age, 5%–10% of female BC cases are related to germline mutations in BRCA1 and BRCA2 genes, while 7% of BRCA2 mutations are associated with male BC.[1],[4],[5],[6] Moreover, mutations in either BRCA1 or BRCA2 increase the susceptibility for the development of ovarian cancer.[4],[7],[8]

Histologically, BC is a heterogeneous disease that can be categorized broadly into invasive or in situ carcinomas. Invasive carcinoma can be subsequently divided into six subtypes: tubular, ductal lobular, invasive lobular, infiltrating ductal, mucinous, and medullary.[9] In situ carcinomas, on the other hand, can be divided into two subtypes: ductal and lobular.[9] At the molecular level, the different subtypes of BC can be branded as basal-like, luminal, human epidermal growth factor receptor 2/estrogen receptor (HER2+/ER−), claudin-low, normal breast-like, interferon-related, molecular apocrine, and triple-negative.[10],[11] The distinction between these subcategories is based on the expression levels of ER, HER2, vimentin, claudin, and epidermal growth factor receptor, among others.[12],[13] In addition, a correlation between histological analysis and the presence of genetic alterations has been reported. For example, a translocation leading to fusion of ETS-variant gene 6 and neurotrophic tyrosine receptor kinase 3 genes is predominantly observed in secretory breast carcinomas.[14]

Current treatment paradigm

Increased awareness of cancer screening technologies and the relative efficacy of currently available treatments have extended lifespans, reduced mortality rates, and improved quality of life for BC patients.[1] The present treatment paradigm involves first physically removing the malignant tissue, either partially (breast conserving) or fully (mastectomy).[1] Following surgery, the person is subjected to chemotherapy or radiation with the intent to eradicate remaining cancer cells. These therapies are chosen based on the BC subtype. For example, the preferential treatment for hormone receptor (HR)-related BC is to inhibit or suppress: (1) the production of hormones from ovary (i.e., goserelin), (2) the reuptake of estrogen (i.e., tamoxifen), and (3) the conversion of androgens to estrogens (i.e., letrozole).[10] Conversely, triple-negative BC, the most aggressive BC subtype, exhibits a 22% response rate to conventional chemotherapy treatments as well as a higher probability for metastasis and relapse.[10]

Radiation is used after the surgical removal of cancerous breast tissue, improving the lifespan of patients.[15] According to the BC organization, there are currently three essential radiotherapies used for the treatment of BC: External whole breast radiation, internal radiation, and intraoperative radiation. The effect these radiotherapies exert on BC is detailed in the following sections.

  Signaling Pathway Alterations After Radiation Top

Ionizing radiation (IR) directly kills cancer cells through the induction of double-strand DNA breaks, leading to apoptosis or inhibition of proliferative capacity through mitotic arrest.[16],[17],[18] In addition, radiation acts on the tumor microenvironment, impairing endothelial cell function and induced apoptosis.[19] Furthermore, an inflammatory response is known to be present after radiation, activating the innate immune response to which tumor cells respond evasively.[20],[21] IR acts through activation of p53 pathway, resulting in changes in cell cycling, senescence, apoptosis, or DNA repair.[17] IR can also target BC cells in p53-independent pathways such as activation of the death receptor pathway.[22] IR can also target BC cells through autophagy.[23] Autophagy is a mechanism by which a cell can replace its damaged organelles; therefore, this process can both support and inhibit cancer cell survival.[24] Autophagy regulates p53 through a feedback mechanism in which p53 activates autophagy which, subsequently, suppresses p53.[25] In a recent in vitro study, it was shown that radiation can also increase microRNA (miRNA)-199-5a which directly targets autophagy on IR treatment.[26] Radiotherapy can induce autophagy in BC cells through phosphatidylinositol-3-kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR) pathway.[23],[27] In a separate study, it was shown addition of mTOR inhibitor radiosensitized the BC cells by reducing the mitochondrial membrane potential.[28] Therefore, using radiotherapy alone can reduce its efficiency, but combining it with other drugs/treatment has the ability to increase its efficiency.

  Cancer Stem Cells and Radiation Top

BC is comprised of a relatively small population of cycling quiescent subpopulation with stem cell-like properties showing self-renewal and is responsible for tumor initiation with a heterogeneous population of tumor cells. This population is generally referred as cancer stem cells (CSCs). This population remains untargetable despite advancements made in BC treatment.[29],[30],[31],[32],[33] There are several markers reported in the literature for BC such as CD44+/CD24−.[34] However, it appears that this population has been shown to be heterogeneous, leading to the field selecting cells based on the expression of stem cell genes Nanog and Oct4.[35]

Increasing clinical evidence supports that CSCs are important for cancer resurgence and relapse.[32],[33],[36],[37],[38] As the name suggests, CSCs share phenotypic and functional similarity with normal, healthy stem cells.[39],[40],[41] However, the origin of CSCs has been a matter of debate in the field. One widely accepted theory suggests that normal stem cells undergo series of mutation to acquire CSC-like state, whereas a competing theory purports that a differentiated normal or cancer cell undergoes series of mutations to acquire stem cell-like state through the process of dedifferentiation.[35]

Cancer stem cells

Recent studies have shown that chemotherapy and radiation target a significant number of cancer cells within the tumor bulk, leaving behind a small radioresistant population of cancer cells.[37],[38],[42] CSCs are inherently radioresistant, but not all radioresistant cells are CSCs.[43],[44] Recent studies have shown that some of these resistant nonstem cell populations of cancer cells have potential to subsequently acquire a CSC-like state.[43],[44] The exact mechanism for radioresistant cells to transition into a CSC-like state remains unclear. However, there are several CSC-related processes that are upregulated in radioresistant cells.[44],[45],[46],[47] For instance, radioresistant cells generally show increased self-renewal and DNA damage repair potential.[31] Over the past decade, different genes and signaling cascades associated with the stem cell-like behavior have been thoroughly studied in CSCs, such as Oct4A, Nanog, aldehyde dehydrogenase (ALDH) genes, Notch, and genes linked to the Wnt pathway.[39],[43],[48],[49] Indeed, the literature indicated an increase in the aforementioned pathways in radioresistant cells.[44] In an in vitro study with BC cell lines and cells from primary source indicated that radiation was able to upregulate all reprogramming transcription factors that are used in generation of induced pluripotent stem cells – Oct4, Sox 2, Nanog and Klf4 through Notch-dependent pathway.[42] The findings in this paper suggested that radioresistance can reprogram cells into CSCs and this may occur in already transformed cells and by healthy nearby cells. Increased copy number of Oct4 and Sox 2 was thought to be responsible for radiation-induced CSC formation.[42] In an in vitro model, the application of a pan-ALDH inhibitor, disulfiram, was able to inhibit radiation-induced CSC formation through downregulation of nuclear factor kappa B (NF-κB).[50] The Notch signaling pathway plays an important role in stem cell renewal and maintenance.[51] γ-secretase is an enzyme responsible for cleaving the Notch receptor, which releases Notch intracellular domain (NICD).[51] Then, the NICD translocates to nucleus and transcriptionally regulates several genes that may play an important role in dormancy of a cell.[51] In a separate study with BC cells, combination of γ-secretase inhibitors with radiation was shown to reduce the CSC subpopulation,[46] thus suggesting combinatorial treatment approaches for targeting BC will be more productive way of targeting these cancer cells.

As indicated above, radiation can increase cancer clearance. However, based on the discussion above, it is likely that radioresistance could worsen the patient's prognosis. Hormones such as estrogen, progesterone, and herceptin have been studied to show clear roles for the development and maintenance of the healthy mammary gland.[52],[53],[54] As such, unbalanced hormone levels, either natural (due to mutation) or as a result of treatment, can lead to cancer development.[55] In these cases, the combination of radiation and hormone therapies can be more detrimental to the patient.[55] In a study performed with radiosensitive BC cells, stimulation with hormones lead to increased resistance of the CSC population.[55] The BC cell line T47D, upon stimulation with progesterone, either directly upregulated miRNAs such as 328 and 98-5p or downregulated miRNAs such as 22-3p and 29c-3p.[55] These miRNAs regulate transcription of cell cycle and stem cell-associated genes. Further, on irradiating the progesterone-stimulated T47D cells, the level of let-7 family of miRNA was downregulated in ALDH+ cells.[55] The downregulation/loss of let-7 family of miRNA has been known to upregulate the pluripotency genes.[56] Thus, these findings suggest,– at least in an in vitro two-dimensional model, that the BC cells can acquire a more stem cell-like state upon receiving a combination of radiation and hormone therapy.[55]

Epithelial-to-mesenchymal transition

The process of dedifferentiation of normal breast cells and BC cells occurs through epithelial-to-mesenchymal transition (EMT).[57],[58],[59],[60] During embryonic development, EMT is a process utilized by embryonic stem cells to change from epithelial to mesenchymal lineage.[60] Similarly, when normal breast epithelial cells undergo EMT, they acquire CSC-like properties by undergoing dedifferentiation.[60] Thus, EMT markers are upregulated in CSCs.[60] EMT also helps these BC/stem cells to metastasize to different organs where they either form a secondary tumor or remain dormant until conditions are favorable for them to undergo rigorous cell division.[61]

In a recent study, BC cells were first stimulated with transforming growth factor beta (TGF-β) to undergo EMT, and then, both the stem cells and nonstem cells were isolated and introduced to IR.[45] The CSCs resisted the radiation by reducing the polyploidy ratio and blocking the cells mostly at G2M phase, preventing mitotic catastrophe and increasing its clonogenicity.[45] In another study using different BC lines, MDA-MB-231, MCF-7, and T47D, radioresistant cells showed increased potential to form colonies compared to the parental cells and increased expression of stem cell and EMT-associated markers.[62] These findings further support the link between radioresistance and stemness. The role of oncogene Bmi-1, also a stem cell-associated gene, has been widely studied in the field of CSC maintenance. Overexpression of Bmi-1 can increase cell migration.[63] Studies have shown that radiation regulates EMT through Bmi-1 and the PI3K/Akt cascade.[47] EMT induction was reduced following radiation exposure when BC cells were treated with PI3K/Akt inhibitor, whereas EMT was completely hampered, with or without radiation exposure, in BC cells with shRNA knockdown of Bmi-1.[47] Further, it has been shown that women who received IR during childhood had an increased risk of developing BC, supporting early radiation as a risk factor.[64],[65]

  Radiation-Associated Nonspecific Effects Top

A major issue associated with radiation therapy is that it increases the already hypoxic tumor microenvironment, creating an even more suitable environment for CSC survival.[66] In this context, CSCs have reduced numbers of DNA breaks that could counter radiation-induced death.[66] However, nonspecific effects of radiation have also been reported to improve clearance of cancer cells within the tumor volume.[22] There are three distinct nonspecific long-term effects associated with radiation: bystander, abscopal, and cohort effects.[67]

Bystander effect

The bystander effects are limited to neighboring cells around the irradiated tumor.[67] The bystander effect on CSCs has been shown in many different forms of cancer, but this effect in BC needs more experimental validation.[68] It has been shown that exposure of BC cells to low-dose radiation leads to release of soluble TNF-related apoptosis-inducing ligand and tumor necrosis factor-alpha, resulting in changes in the tumor microenvironment and increased apoptosis in BC cells through bystander effect.[22] Furthermore, a study performed using MCF7 BC cells exposed to gradient irradiation showed better clearance of BC cells through TGF-β1, reactive oxygen species, and nitric oxide-mediated pathways.[69] However, a mathematical model based on the previous radiation data has shown that sparsely IR, such as g-irradiation, can promote the formation of CSCs, whereas dense radiation, such as neutrons, promotes the formation of preexisting CSC clones and this occurs through bystander effect.[68],[70],[71]

Abscopal effect

Radiation therapy can affect cells outside the irradiated volume, far from the treatment site, due to a phenomenon commonly known as the abscopal effect.[67] Since the abscopal effect targets distant cells, this limits the studies that can be conducted in a clinical setting. Thus, further studies are needed to dissect a mechanism for this effect. Based on the current clinical data, it is believed that the abscopal effect is helpful in improved clearance of cancer cells by activation of immune cells against cancer.[72] In a clinical trial (NCT02474186) within a cohort of BC patients, the combination of immunotherapy with radiation therapy significantly combatted BC through abscopal effect.[72] In a separate case report, it was shown that a 64-year-old women with metastatic BC showed regression of tumor mass 10 months after localized radiation therapy with no further reporting of tumor.[73]

Cohort effect

The cohort effect of radiation targets nonspecific cells within the tumor volume.[67] For instance, a high dose of localized radiation may affect the nearby tumor cells through transmission of low-dose signals into the surroundings.[69] Thus, the cohort effect increases the odds of clearance of tumor cells. In a recent study, MCF7 BC cells were subjected to a gradient of radiation in which the cells in the center of the dish receive the highest dose of irradiation and the dose decreases toward the edge of the plate. This radiation approach induced increased rates of cell death in MCF7 compared to uniform dose.[69] Similar to the abscopal effect, the molecular mechanism underlying this effect has yet to be elucidated.

  Radiation-Induced Autophagy Top

Autophagy is a process by which the cells use intracellular processes to survive. This can occur by the cells eliminating the damaged protein, molecules, and organelles as well as preserving energy during stress.[74] Cellular stress initiates autophagosome formation which then fuses with lysosome to form autophagolysosome.[74] The enzymes within lysosomal compartment lead to degradation of the damaged materials.[74] This prevents the cells from accumulating toxic agent, although autophagy can also induce cell death with excessive stress.[74] Thus, the complex molecular mechanisms of autophagy can also prevent cancer and benefit cancer cell survival.[24]

Similar to other source of stress, one of the common effects of radiation on BC cells is the induction of autophagy. This can either cause cancer cell death or maintain their survival.[24] Indeed, radiation-induced autophagy was experimentally demonstrated in the BC cell line, MCF-7.[28] Radiation, when introduced in combination with rapamycin, an mTOR pathway inhibitor (autophagy inhibitor), was able to increase cell death in MCF7. The mechanism by which this occurred is through mitochondrial hyperpolarization and p53 phosphorylation.[28]

A programmed cell death is through caspase − 3/7. The combinatorial treatment of the cell cycle inhibitor, tunicamycin, and radiation led to increased caspase 3.[75] Similar increase has been shown in MCF-7 cells through the activation of autophagy.[75] Overexpressing autophagy-associated genes, ATG5 and Beclin-1, in BC cells led to an increase in radiation-mediated cell death.[76] A possible mechanism by which autophagy induces cell death upon radiation is p53-mediated damage-regulated autophagy modulator (DRAM).[77],[78] Silencing of DRAM decreased radiation-induced cell death, independent of p53.[77],[78]

In contrast to its tumor suppressive role, autophagy can also support tumor survival.[79] An in vivo mouse model inhibited autophagy-associated genes ATG5, ATG7, and FIP200 and this led to reduced malignancy of BC.[79] FIP200 deletion drastically downregulated cell cycle proteins and this prevented early tumor initiation potential of BC cells.[79] Even in hereditary-associated BC mice model, autophagy disruption-reduced PALB2 (germline mutation) that is generally linked to tumor initiation.[80] These findings are in line with other studies showing autophagy being associated with stem cell survival.[80] During stress, stemness is maintained by induction of autophagic pathway to eliminate toxic molecules.[81] Within a tumor microenvironment, autophagy-associated gene ATG can maintain CSCs.[82],[83] Blocking of autophagy-associated genes by siRNA strategy has led to reduced radioresistance.[23]

A Phase I/II clinical trial in glioblastoma with autophagic inhibitor, hydroxychloroquine, when given as a combinatorial treatment with radiotherapy and/or chemotherapy, comparatively improved the patient prognosis.[84] One of the possible mechanisms by which autophagy induces BC dormancy is by regulating IL-6, since this cytokine has been shown to maintain the CSC population.[85] Radiation-mediated CSC survival has been discussed above, within another section. Radiation-mediated stress acts as inducer of autophagy which can be either tumor suppressor or initiator, depending on the tumor microenvironment. Thus, further dissecting the role of autophagy in BC progression needs to be done for improved treatment.

  Radiation-Mediated Epigenetics Changes Top


The term “epigenetics” refers to heritable changes occurring within a cell without alterations of the DNA sequence. Chromatin modifications are implicated in cellular homeostasis by regulating gene expression and providing cellular identity. The “epigenome” has emerged as an important factor in the development of cancer and progression. Although alterations of the DNA sequence are a hallmark of oncogenesis, it has become evident that the epigenome is also involved in this process.[86],[87] Modifications to the DNA and the histones confer plasticity to cancer cells, thereby promoting survival within particular niches.[86] As epigenetic changes are reversible, they serve as a plausible avenue for the study of oncogenesis and possible eradication of cancer. The subsequent discussion in this section expands on the specific method of epigenetic links to radiation.

DNA methylation

DNA methylation is one of the modifications that have been extensively studied in the context of gene regulation. Insertions of a methyl group to cytosines, such as 5-methylcytosine, are associated with gene repression.[88] Methylation controls important cellular processes, such as cell cycle, DNA repair, and apoptosis. In cancer, these modifications work together to promote cancer cell survival and suitability for the metastatic microenvironment.[86],[89],[90] In addition, global hypermethylation is observed in cancer and in several tumor suppressor genes.[87] The proteins mediating these changes are termed methyltransferases or demethylases. Methylations usually occur in regions of the DNA consisting of cytosines followed by guanines, known as CpG islands.[86],[87],[88]

DNA methylation patterns have served as an approach to improve BC prognosis.[91],[92] Epigenetic signatures in DNA caused by the DNA methyltransferase protein 1 (DNMT1) mediate maintenance of the tumor by supporting breast CSCs.[93] Interactions between DNMT1 and enhancer of zeste homolog-2 lysine methyltransferase promote EMT in triple-negative BC cells by suppressing the gene wwc1, which participates in the Hippo pathway.[94] Furthermore, compelling evidence suggests that hypomethylation of stem cell-associated genes stimulates BC progression and migratory properties.[95] Hence, methylation is an important regulatory process that aids in the survival and advancement of BC cells.

Histone modifications

Chromatin is composed of histone octamers wrapped by 147 bp of DNA, forming the core unit, or nucleosome. The histones H2a, H2b, H3, and H4 are susceptible to epigenetic modifications that contribute to the diversity of the epigenome through 16 currently identified alterations.[87],[88] Histone modifications can cause either activation or repression of gene expression. For example, acetylation of lysine or arginine residues activates gene expression due to the neutralization of the positive charge of these amino acids, whereas methylation mostly correlates with transcriptional repression.[88] Importantly, the crosstalk between histone modifications and DNA methylation is relevant to cellular identity and control of gene expression, providing complexity to the role of epigenetics in physiological and pathophysiological processes.[86],[87]

The biological function of histone deacetylases (HDAC) has been widely examined with respect to cancer. Several studies have revealed a fundamental role of HDACs in the maintenance of a CSC-like phenotype in breast and ovarian tumors.[96] Importantly, it was demonstrated that HDAC6 is necessary for the immunosuppressive properties of BC-associated fibroblasts, leading to recruitment of regulatory T-cells and myeloid-derived suppressor cells.[97] Further, overexpression of HDAC1 causes reduction of ERα and increases proliferation of ER + BC.[98] Overall, these seminal studies prove the importance of epigenetic factors in BC dissemination.

  Relevant Therapy Top

Radiation remains a conventional regimen for cancer treatment. It is known that radiotherapy alters DNA methylation patterns, conferring radioresistance to cancer cells.[99] In addition, dose-dependent hypomethylation of DNA, mediated by radiotherapy, can lead to downregulation of DNMTs, resulting in genomic instability.[90],[100] Changes affecting the DNA damage response, apoptosis, and cell cycle pathways are prevalent after radiation, partly through methylation of the genes involved in these processes.[101] Moreover, immune signaling pathways in BC cells are affected by irradiation through NF-κB pathway regulation.[102]

Similar findings have been reported in other cancer models regarding the effects of radiation in epigenetics. In colon cancer cells, radiation-induced hypomethylation of genes known to be dysregulated during oncogenesis.[103] The hypomethylation marks encountered on the promoter regions of these genes were attributed to decreased levels of DNMT1/3b.[103] In addition, irradiation stimulates the acquisition of a CSC-like phenotype of prostate cancer cells.[104] Interestingly, radiation caused H3 methylation of the promoter region of ALDH1A1, preventing apoptosis and enhancing maintenance of the CSC phenotype.[104] Considering these findings, it is imperative to grasp the role of the epigenome during oncogenesis and cancer progression. Moreover, further investigation is required to fully understand the impact of radiation on epigenetic factors and how these alterations may enhance a CSC phenotype.

In light of the detrimental effects of radiotherapy on cancer epigenetics, discussed above, there are effects to use the scientific information to develop counteractive treatments. As an example, recent studies have demonstrated the benefits of combinatorial therapies that utilize both epigenetic inhibitors and radiation.[90] In addition, an epigenetic drug, consisting of dypiridamole and the antifolate TMCG, prevented H4K20 and H3K79 methylation marks, resulting in radiosensitization of BC cells by inhibition of DNA repair processes.[105]

Histone deacetylases inhibitors: Epigenetic-modifying drugs

HDAC inhibitors (HDACis) are therapeutic agents that promote gene transcription and chromatin relaxation by supporting the accumulation of acetylation marks. These “epi-drugs” have shown promising outcomes as anticancer therapeutics due to their cytotoxic activity, partly by inducing apoptosis, autophagy, and cell cycle arrest.[106] Four classes of HDACi have been described, such as hydroxamic acids, cyclic peptides, aliphatic acids, and benzamides.[107] Vorinostat, a hydroxamic acid, was the first HDACi approved by the FDA for the treatment of cutaneous T-cell lymphoma (CTCL).[108] This agent specifically inhibits Zn(II)-dependent Class I and II HDACs.[106] Cyclic peptides are the most structurally complex and diverse class of HDACi that allowed for interaction with multiple motifs within the HDACs enzymatic portion.[109] Currently, romidepsin (FK-228), a cyclic tetrapeptide, is being utilized for the treatment of CTCL.[110] Aliphatic acids are considered weak HDACi by excelling their function at millimolar concentrations.[106],[111] Furthermore, benzamides are mostly Class I HDACis, affecting primarily HDAC 1 and 3.[112] The structural composition of these compounds is essential for their interactions with different types of HDACs.

Histone deacetylases inhibitors as a therapeutic for breast cancer treatment

In BC, HDACis can modulate the epigenomic profile of cancer cells to promote apoptosis and cellular senescence. A recent study demonstrated that the HDACi, trichostatin A, increased miR-125a-5p, resulting in intrinsic apoptosis and inhibition of HDAC5.[113] Further, the HDACis butyrate and panobinostat have been shown to upregulate miR-31 by downregulating Bmi-1 to enhance cellular senescence in BC cells.[114] Furthermore, short-term exposure of vorinostat is implicated in the induction of DNA damage and halting of the replication machinery.[115] Importantly, a novel HDACi, YF479, displayed antitumor activity and prevented lung metastasis of BC cells.[116] These studies demonstrate the efficacy of HDACi's in the treatment of BC and their implications in possible eradication of the disease.

In addition, HDACis have become a promising therapy in combination with chemotherapy and radiation.[117] Valproic acid, a HDACi, coupled with whole-brain radiation therapy resulted in overall survival of BC patients with brain metastases.[118] Moreover, vorinostat sensitizes BC cells to radiotherapy and enhances cell death.[119] Combinatorial treatment also promoted autophagy and cytotoxicity and prevented cell survival.[99]

An ongoing double-blind Phase III clinical trial utilizes endocrine therapy in conjunction with the HDACi entinostat in BC patients with metastatic HR-positive and HER2−, previously treated with aromatase inhibitors.[102] This goal of this study is to improve the overall survival of metastatic BC by regulating resistance to endocrine therapy with HDACi.[120] This investigation is based on a Phase II clinical trial that improved progression-free and overall survival as well as patient's tolerance to the combinatorial therapy.[121] Despite the success of the use of HDACi's with adjuvant treatment, the application of these agents as a monotherapy for the treatment of cancers remains arguable. For example, a Phase II clinical trial used vorinostat as a therapeutic for Stage IV BC resulted in termination due to adverse outcomes (clinicaltrials.gov). Nonetheless, ten active clinical studies using HDACis are currently recruiting patients, demonstrating the potential of these agents in the treatment of BC (clinicaltrials.gov).

Prospects of epigenetic drugs on cancer stem cells

The “epigenome” is involved in the acquisition and maintenance of a CSC phenotype.[122] The use of epigenetic therapeutics has become relevant for the targeting of CSCs, preventing tumor formation and cancer relapse. These agents are essential for differentiating CSCs to enhance sensitivity to adjuvant therapy for cancer eradication. Recently, a study demonstrated that alterations of the epigenetic profile of ovarian CSCs, mediated by a DNA hypomethylating agent, resulted in the reduction of this population and enhanced sensitization to chemotherapy.[123] Another DNA-demethylating agent promoted chemosensitivity of CSCs by regulating the expression of miR-497.[124] Further, HDAC inhibition is implicated in the reduction of breast CSCs by induction of caspase-dependent apoptosis.[125] Taken together, these studies suggest the importance of epigenetic-modifying drugs in the targeting of CSCs.

  Conclusion Top

The CSC subpopulation of BC cells is primarily the cells responsible for cancer resurgence, leading to poor outcome. The CSCs are quiescent with respect to cell cycle and have been shown to resist conventional therapies, such as radiation.[44],[45],[46],[47] During resurgence, referred as reverse dormancy, the CSCs become cycling activated and develop into a heterogeneous population of cancer cells.[126] In addition, subsets of nonstem cells can be radioresistant and have the potential, as described in this review, to adopt CSC-like features that further contribute to their ability to persist in the body following treatment [Figure 1]. Furthermore, the epigenetic profile of radioresistant cells is critical to their ability to acquire a cycling quiescent, CSC-like phenotype [Figure 1]. Gaining a better understanding of the role of epigenetics in response to radiotherapy is an important parameter in developing more effective therapeutic strategies for the future.
Figure 1: Effect of radiation on breast cancer cells through specific and nonspecific targeting. (a) Specific targeting leads to reduction in tumor volume, survival of resistant cells, formation of cancer stem cell formation (formation repetitive), or epigenetic changes. The latter can lead to radioresistance and/or cancer stem cell formation or reduced tumor volume. The radioresistant or cancer stem cell, later, are relevant to long-term source of metastasis such as recurrence. (b) Nonspecific targeting occurs when the radiation indirectly affects tumor cells or the tumor microenvironment for outcome described as for “A”

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Financial support and sponsorship

This work was funded by the F.M. Kirby Foundation to PR and Fundação de Amparo à Pesquisa do Estado de São Paulo to YN and HU.

Conflicts of interest

There are no conflicts of interest.

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