The Roles of DNA Demethylases in Triple-Negative Breast Cancer

Panjarian, Shoghag; Issa, Jean-Pierre J.

doi:10.3390/ph14070628

Cited by 6 publications

(2 citation statements)

References 91 publications

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“…The role of TET1 in breast cancer is controversial. While some studies indicated that TET1 is a tumor suppressor gene ( 20 , 21 ), others demonstrated that it is an oncogene ( 16 , 32 ). In the current study our results indicate that the picture seems to be more complicated and that the role of TET1 in breast cancer is not black and white.…”

Section: Discussionmentioning

confidence: 99%

TET1 Isoforms Have Distinct Expression Pattern, Localization and Regulation in Breast Cancer

Alzahayqa¹,

Jamous²,

Khatib³

et al. 2022

Front. Oncol.

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TET1 regulates gene expression by demethylating their regulatory sequences through the conversion of 5-methylcytosine to 5-hyroxymethylcytosine. TET1 plays important roles in tissue homeostasis. In breast cancer, TET1 was shown to play controversial roles. Moreover, TET1 has at least two isoforms (long and short) that have distinct expression pattern and apparently different functions in tissue development and disease including breast cancer. We hypothesized that TET1 isoforms have different expression patterns, localization and regulation in different types of breast cancer. To prove our hypothesis, we studied the expression of TET1 isoforms in basal and luminal breast cancer cell lines, as well as in basal and luminal breast cancer animal models. We also studied the effect of different hormones on the expression of the two isoforms. Moreover, we assessed the distribution of the isoforms between the cytoplasm and nucleus. Finally, we overexpressed the full length in a breast cancer cell line and tested its effect on cancer cell behavior. In this study, we demonstrate that while Estrogen and GnRH downregulate the expression of long TET1, they lead to upregulation of short TET1 expression. In addition, we uncovered that luminal cells show higher expression level of the long isoform. We also show that while all TET1 isoforms are almost depleted in a basal breast cancer animal model, the expression of the short isoform is induced in luminal breast cancer model. The short form is expressed mainly in the cytoplasm while the long isoform is expressed mainly in the nucleus. Finally, we show that long TET1 overexpression suppresses cell oncogenic phenotypes. In conclusion, our data suggest that TET1 isoforms have distinct expression pattern, localization and regulation in breast cancer and that long TET1 suppresses oncogenic phenotypes, and that further studies are necessary to elucidate the functional roles of different TET1 isoforms in breast cancer.

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Section: Discussionmentioning

confidence: 99%

TET1 Isoforms Have Distinct Expression Pattern, Localization and Regulation in Breast Cancer

Alzahayqa¹,

Jamous²,

Khatib³

et al. 2022

Front. Oncol.

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“…For example, dysregulation of DNA methylation can promote or maintain the cancer cell stemness, thereby contributing to the pathogenesis of BC [ 8 , 9 ]. Moreover, TNBC patients exhibited widespread genomic hypomethylation, while the buildup of methylation enhanced the risk of BC in postmenopausal women [ 10 , 11 ]. In addition, dysregulation of histone modification also serves as a crucial marker in cancer [ 12 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

KDM5 family as therapeutic targets in breast cancer: Pathogenesis and therapeutic opportunities and challenges

Li,

Wang,

Leung

et al. 2024

Mol Cancer

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Breast cancer (BC) is the most frequent malignant cancer diagnosis and is a primary factor for cancer deaths in women. The clinical subtypes of BC include estrogen receptor (ER) positive, progesterone receptor (PR) positive, human epidermal growth factor receptor 2 (HER2) positive, and triple-negative BC (TNBC). Based on the stages and subtypes of BC, various treatment methods are available with variations in the rates of progression-free disease and overall survival of patients. However, the treatment of BC still faces challenges, particularly in terms of drug resistance and recurrence. The study of epigenetics has provided new ideas for treating BC. Targeting aberrant epigenetic factors with inhibitors represents a promising anticancer strategy. The KDM5 family includes four members, KDM5A, KDM5B, KDM5C, and KDMD, all of which are Jumonji C domain-containing histone H3K4me2/3 demethylases. KDM5 proteins have been extensively studied in BC, where they are involved in suppressing or promoting BC depending on their specific upstream and downstream pathways. Several KDM5 inhibitors have shown potent BC inhibitory activity in vitro and in vivo, but challenges still exist in developing KDM5 inhibitors. In this review, we introduce the subtypes of BC and their current therapeutic options, summarize KDM5 family context-specific functions in the pathobiology of BC, and discuss the outlook and pitfalls of KDM5 inhibitors in this disease.

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