scholarly journals The Roles of DNA Demethylases in Triple-Negative Breast Cancer

2021 ◽  
Vol 14 (7) ◽  
pp. 628
Author(s):  
Shoghag Panjarian ◽  
Jean-Pierre J. Issa
Keyword(s):  
Breast Cancer ◽  
Dna Methylation ◽  
Tumor Suppressor Genes ◽  
Hormone Receptors ◽  
Triple Negative ◽  
Breast Cancers ◽  
Therapeutic Implications ◽  
High Propensity ◽  
Dna Methylation Profile

Triple-negative breast cancers (TNBCs) are very heterogenous, molecularly diverse, and are characterized by a high propensity to relapse or metastasize. Clinically, TNBC remains a diagnosis of exclusion by the lack of hormone receptors (Estrogen Receptor (ER) and Progesterone Receptor (PR)) as well as the absence of overexpression and/or amplification of HER2. DNA methylation plays an important role in breast cancer carcinogenesis and TNBCs have a distinct DNA methylation profile characterized by marked hypomethylation and lower gains of methylations compared to all other subtypes. DNA methylation is regulated by the balance of DNA methylases (DNMTs) and DNA demethylases (TETs). Here, we review the roles of TETs as context-dependent tumor-suppressor genes and/or oncogenes in solid tumors, and we discuss the current understandings of the oncogenic role of TET1 and its therapeutic implications in TNBCs.

scholarly journals Practical Approach to Triple-Negative Breast Cancer

2017 ◽  
Vol 13 (5) ◽  
pp. 293-300 ◽  
Author(s):  
Vijayakrishna K. Gadi ◽  
Nancy E. Davidson
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Hormone Receptors ◽  
Triple Negative ◽  
Early Stage ◽  
Management Strategies ◽  
Growth Factor Receptor ◽  
Breast Cancers ◽  
Epidermal Growth ◽  
Proven Method

Triple negative is a term applied to breast cancers that do not meaningfully express the estrogen or progesterone hormone receptors or overexpress the human epidermal growth factor receptor 2 tyrosine kinase. At present, the only proven method for systemic management of triple-negative breast cancer for both early-stage and metastatic settings is cytotoxic chemotherapy. Here, we provide a comprehensive review of management strategies that are best supported by available data. We also review recent advances most likely to affect treatment of triple-negative breast cancer in the coming years with particular emphasis on targeted agents, biologics, and immunotherapy.

scholarly journals Targeting DNA methylation for treating triple-negative breast cancer

2019 ◽  
Vol 20 (16) ◽  
pp. 1151-1157 ◽  
Author(s):  
Jia Yu ◽  
Jacqueline Zayas ◽  
Bo Qin ◽  
Liewei Wang
Keyword(s):  
Breast Cancer ◽  
Dna Methylation ◽  
Tumor Suppressor ◽  
Triple Negative Breast Cancer ◽  
Targeted Therapies ◽  
Tumor Suppressor Genes ◽  
Dna Methyltransferase ◽  
Triple Negative ◽  
Suppressor Genes ◽  
Dna Methyltransferase Inhibitors

Triple-negative breast cancer (TNBC) accounts for 15–20% of all invasive breast cancers and tends to have aggressive histological features and poor clinical outcomes. Unlike, estrogen receptor- or HER2-positive diseases, TNBC patients currently lack the US FDA-approved targeted therapies. DNA methylation is a critical mechanism of epigenetic modification. It is well known that aberrant DNA methylation contributes to the malignant transformation of cells by silencing critical tumor suppressor genes. DNA methyltransferase inhibitors reactivate silenced tumor suppressor genes and result in tumor growth arrest, with therapeutic effects observed in patients with hematologic malignancies. The antitumor effect of these DNA methyltransferase inhibitors has also been explored in solid tumors, especially in TNBC that currently lacks targeted therapies.

Using epigenetic reprogramming to target triple-negative breast cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e14565-e14565
Author(s):  
D. Sharma ◽  
B. B. Knight ◽  
R. Yacoub ◽  
T. Liu ◽  
L. Taliaferro-Smith ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Hormone Receptors ◽  
Triple Negative ◽  
Combined Treatment ◽  
Brdu Incorporation ◽  
Breast Cancers

e14565 Background: The outcome for patients with breast cancer has been significantly improved by the use of targeted agents. The prognosis of triple negative (TN) breast cancers, which do not express hormone receptors (ER, PR) or Her2, is poor, because of an aggressive clinical course and lack of targeted therapeutic agents. Epigenetic silencing of specific genes has been observed in breast cancer and some of these genes are more important due to available targeted therapies such as ER. Since all endocrine therapies are designed to block ER function in some way, the identification of new therapies or strategies that could sensitize TN breast cancers to existing endocrine therapy could provide a revolutionary means of treating this aggressive subtype of cancer Methods: We examined the efficacy of combined treatment of HDAC inhibitor LBH589 and DNMT inhibitor decitabine to regenerate ER and PR in TN breast cancer cells using RT-PCR and immunoblotting. Changes in growth and proliferation of TN breast cancer cells in response to LBH589 and decitabine treatment were determined by XTT, BrdU incorporation and colony formation assay. Changes in apoptotic proteins were determined by western blotting. Athymic nude mice were used to establish pre-clinical models for TN breast cancer cells and effectiveness of combined treatment of LBH589 and decitabine was determined. Tumors biopsies were analyzed for ER and PR re-expression by western blot analysis and immunohistochemistry at the end of the treatment. Results: Combined treatment of LBH589 and decitabine resulted in re-expression of ER and PR in TN breast cancers in vitro and in vivo. Although re-expression of ER and PR were noted following LBH589 treatment alone, re-expression was more robust with the combination. TN breast cancer cells showing re-expressed ER can be targeted with tamoxifen. Tamoxifen inhibits growth of TN breast cancer cells re- expressing ER by triggering apoptosis. Conclusions: The importance of epigenetic events such as DNA methylation and HDAC inhibition in tumor progression is becoming increasingly evident. A trial evaluating the ability of LBH589 and decitabine to re- express ER, which can then be targeted by tamoxifen, is planned in patients with metastatic TN breast cancer. No significant financial relationships to disclose.

A retrospective review of demographics and stage of triple-negative breast cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e11553-e11553
Author(s):  
F. N. Rana
Keyword(s):  
Breast Cancer ◽  
Family History ◽  
Triple Negative Breast Cancer ◽  
Hormone Receptors ◽  
Triple Negative ◽  
Smoking Status ◽  
Linear Trend ◽  
Published Data ◽  
Breast Cancers ◽  
Demographic Risk

e11553 Background: Triple negative breast cancer (TNBC) is a recently recognized subtype of breast cancer, notable to metastasize early. It accounts for 15–20% of all breast cancers, and is more prevalent in African-American and Hispanic women, and women younger than 40 years of age. Continual decline in breast cancer deaths since 1990 has been attributed to earlier detection, better treatment including hormonal blockade in estrogen- and progesterone-receptor positive cancers, as well as the addition of Trastuzumab, a monoclonal antibody directed against the Her2/neu receptors. These hormone receptors are not found in TNBC, and therefore the traditional targets for endocrine manipulation cannot be therapeutically exploited. While lower socioeconomic status and racial predisposition to this disease have been observed, there exists a paucity of research into other demographic risk factors. We reviewed data between January 2000 to December 2005 from our tumor registry with particular attention to age, race, family history, tobacco use, and stage of presentation, comparing this subset of patients (n=39) to other records (n=303). We included only those patients in whom the status of all three receptors were recorded. Results: Comparisons were made for TNBC vs non-TNBC patients respectively as follows: mean age (59.87± yrs vs 60.09±yrs). Analysis using χ2 test (χ2=0.855) and CMH test for Linear Trend analysis (p=0.47) showed no difference in percentages in association with the 5 stages or TNBC status and no linear trend respectively. Conclusions: This data suggests that at our institution, TNBC is less prevalent (12.87%) than estimates of 15- 20% published in other studies. There was no difference in age at diagnosis (p=0.92), with black patients more likely to have TNBC (p=0.004, OR=2.75). There was no significant association between smoking status and TNBC (p=0.43). There was no significant association between a family history of cancer and TNBC (p=0.8384). When accounting for samples size, TNBC was as prevalent as non TNBC at all stages of diagnosis. These results differ from other published data and may reflect differences in statistical analysis. No significant financial relationships to disclose.

scholarly journals A Review of the Potential Role of Human Cytomegalovirus (HCMV) Infections in Breast Cancer Carcinogenesis and Abnormal Immunity

Cancers ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 1842 ◽  
Author(s):  
Jürgen Geisler ◽  
Joel Touma ◽  
Afsar Rahbar ◽  
Cecilia Söderberg-Nauclér ◽  
Katja Vetvik
Keyword(s):  
Breast Cancer ◽  
Human Cytomegalovirus ◽  
Triple Negative ◽  
Breast Tumors ◽  
Active Role ◽  
Gene Products ◽  
Breast Cancers ◽  
Wide Range

Previously recognized classical human onco-viruses can regulate complex neoplastic events, and are estimated to play a role during carcinogenesis in 15–20% of cancer cases. Although the DNA and gene products of several viruses have been found in breast tumors, none of the classical onco-viruses have definitely been linked to the initiation of breast cancer. However, recent evidence shows that human cytomegalovirus (HCMV) gene products are found in >90% of tumors and metastases of breast cancers, and their increased expression can be correlated to a more aggressive breast cancer phenotype. Supporting the active role of HCMV in breast cancer, a specific HCMV strain, HCMV-DB, was recently shown to exert oncogenic transformational activity in breast epithelial cells in vitro, and to give rise to fast-growing, triple-negative breast tumors when injected into immune deficient mice. The same observation holds true for clinical studies implying increased HCMV protein expression in triple negative breast cancer biopsies. In addition to functionally being able to hijack tumor-promoting cellular events, HCMV is known to exhibit a wide range of immunosuppressive effects, which can have radical impact on the tumor microenvironment. HCMV infected cells can avoid recognition and elimination by the immune system by orchestrating polarization of immunosuppressive type II macrophages, preventing antigen presentation, by expressing T cell inhibitory molecules, and possibly, by the induction of regulatory T (Treg) cell responses. These actions would be especially deleterious for the antigenic activation and proliferation of tumor specific CD8+ cytotoxic T lymphocytes (CTLs), whose effector functions have recently been targeted by successful, experimental immunotherapy protocols. The recognition of alternative causes and drivers of breast cancer is a pivotal research topic for the development of diagnostics and novel, effective preventive and therapeutic strategies targeting both tumor cells and their microenvironments.

Triple Negative Breast Cancer Pathologic Diagnosis and Current Chemotherapy Treatment Options

2014 ◽  
Vol 10 (01) ◽  
pp. 35 ◽  
Author(s):  
Bernardo L Rapoport ◽  
Simon Nayler ◽  
Georgia S Demetriou ◽  
Shun D Moodley ◽  
Carol A Benn ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Hormone Receptors ◽  
Triple Negative ◽  
Treatment Options ◽  
Single Agent ◽  
Metastatic Breast ◽  
Complete Response ◽  
Breast Cancers ◽  
Metastatic Setting

Triple negative breast cancer (TNBC) comprises 12–20 % of all breast cancers and are a heterogeneous group of tumours, both clinically and pathologically. These cancers are characterised by the lack of expression of the hormone receptors oestrogen receptor (OR) and progesterone receptor (PR), combined with the lack of either overexpression or amplification of the human epidermal growth factor receptor-2 (HER2) gene. Conventional cytotoxic chemotherapy and DNA damaging agents continue to be the mainstay of treatment of this disease in the neoadjuvant, adjuvant and metastatic setting. The lack of predictive markers in identifying potential targets for the treatment of TNBC has left a gap in directed therapy in these patients. Platinum agents have seen renewed interest in TNBC based on an increasing body of preclinical and clinical data suggesting encouraging activity. However, comparisons between chemotherapy regimens are mostly retrospective in nature and the best agents or drug combinations for TNBC have not been established in prospective randomised trials. Numerous studies have now shown that TNBC has significantly higher pathological complete response (pCR) rates compared with hormone receptor positive breast cancer when treated with neoadjuvant chemotherapy, and pCR correlates well with better outcomes for these patients. Patients with TNBC account for a larger number of deaths in the setting of metastatic breast cancer. There is no preferred treatment for the first-line metastatic setting. Although individual agents are recommended, given the often aggressive nature of TNBC and the presence of extensive visceral disease, the use of a combination of drugs, rather than a single agent, is often advocated. This review article will outline the pathological diagnosis of TNBC and the treatment options available to these patients in the neoadjuvant, adjuvant and metastatic setting, including an assessment of future directions of treatment.

Epigenetic profiles capturing breast cancer stemness for triple negative breast cancer control

Epigenomics ◽  
2019 ◽  
Vol 11 (16) ◽  
pp. 1811-1825 ◽  
Author(s):  
Xiaofeng Dai ◽  
Rong Ma ◽  
Xijiang Zhao ◽  
Fengfeng Zhou
Keyword(s):  
Breast Cancer ◽  
Dna Methylation ◽  
Triple Negative ◽  
Cancer Control ◽  
The Other ◽  
Breast Cancer Stem Cells ◽  
Breast Cancers ◽  
Cancer Stemness ◽  
Cancer Heterogeneity ◽  
Breast Cancer Control

Aim: Triple-negative breast cancers (TNBCs) contain a higher percentage of breast cancer stem cells (BCSCs) than the other subtypes and lack effective yet safe-targeted therapies. We would like to unveil genes relevant to the therapeutic control of breast cancer stemness at the epigenetic level. Methods: We sequenced the transcriptome of BCSCs isolated from TNBCs, identified genes differentially expressed in these cells and subjected to DNA methylation and established the Bayesian network as well as interactions out of them. Results & conclusion: We presented a core epigenetic BCSC gene panel consisting of eight genes that can be used for BCSCs and TNBCs identification, and revealed the dominant roles of FOXA1 and GATA3 in orchestrating breast cancer heterogeneity and stemness.

scholarly journals An institutional review of tumour biology of breast cancer in young Nepalese women

2017 ◽  
Vol 18 (2) ◽  
pp. 16-19
Author(s):  
Bikash Nepal ◽  
Yogendra Singh ◽  
Prakash Sayami ◽  
Gita Sayami
Keyword(s):  
Breast Cancer ◽  
Young Women ◽  
Hormone Receptors ◽  
Triple Negative ◽  
Locally Advanced ◽  
University Teaching ◽  
Breast Cancers ◽  
Younger Patients ◽  
Younger Women ◽  
Tumour Biology

Introduction: Breast cancers in less than 40 years of age group usually present with aggressive biology and has poor prognosis. The aim of this study was to see clinic-pathological and hormone receptors of breast cancers in young women and compare with less than 40 year age group.Methods: Prospective analysis of 97 breast cancer in patients less than 40 years out of total 373 patients (26%) over a period of 8 years (2007 Jan to 2014 Dec) was carried out at the Department of Surgery, Tribhuvan University Teaching Hospital, Kathmandu, Nepal.Result: Among the young women diagnosed with breast cancer, the mean age was 34.5±6.2 years. Mean tumour size was larger in younger women (5±2.5 vs 4.5±2.4 cm). Locally advanced disease was higher in younger patients (55% vs 47%). Lymphatic and vascular invasions were higher (63% vs 35% and 40% vs 25%). Grade II and III tumours was higher (56% vs 25%). ER, PR and HER2 positivity was detected in 46.9%, 48.9% and 28.9% respectively. Significant lower ER or PR expression (34.5% vs 54%) was seen in younger women, p=.002.Triple negative tumours (ER -ve, PR -ve and HER2 -ve) was proportionately higher in younger patients (23% vs 13.7%, p=.043).Conclusion: Young Nepali women presents one quarter of all female breast cancers, more frequently locally advanced with aggressive tumour biology like ER/PR negative and triple negative breast cancers. Journal of Society of Surgeons of Nepal, 2015; 18 (2), page: 16-19

scholarly journals Molecular Prognostic and Predictive Markers in Triple - Negative Breast Cancer

2021 ◽  
Author(s):  
Marketa Koleckova ◽  
Katherine Vomackova ◽  
Zdenek Kolar
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Hormone Receptors ◽  
Triple Negative ◽  
Molecular Subtype ◽  
Menopausal Status ◽  
Breast Cancers ◽  
Biological Behaviour ◽  
Erbb2 Protein ◽  
Apoptosis Gene

Triple-negative breast cancer (TNBC) is defined as a molecular subtype of breast cancer that lacks expression of hormone receptors (oestrogen and progesterone receptor) and HER2/neu/ErbB2 protein. It accounts for 15–20% of all invasive breast cancers. The occurrence of TNBC is often associated with younger age at the time of diagnosis and pre-menopausal status, early onset of menarche, higher body mass index (BMI) in the pre-menopausal period, race and ethnicity (African, Hispanic) and the presence of germline mutation in the BRCA1/2 genes or somatic mutation in the TP53 or PTEN genes. TNBCs are specific in its aggressive biological behaviour, shorter interval to disease progression and more frequent relapse within five years (19 to 40 months). The most of TNBCs are represented by high-grade invasive carcinomas of no special type (NST) with high proliferation index measured by Ki-67 nuclear expression, followed by metaplastic carcinomas, secretory carcinomas, and adenoid cystic carcinomas. Genetical and morphological heterogeneity inside TNBC is responsible for the higher frequency of primary and secondary resistance to systemic therapy. The scope of this chapter is to summarise the potential therapeutic agents involved in regulation of cell proliferation, migration, angiogenesis, apoptosis, gene expression and DNA damage or immune response. The insight into this issue is essential for the setting of the optimal chemotherapy regimen and targeted therapeutic strategy.

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