Hypomethylating Agent Azacitidine Is Effective in Treating Brain Metastasis Triple-Negative Breast Cancer Through Regulation of DNA Methylation of Keratin 18 Gene

AbstractBrian metastasis, which is diagnosed in 30% of triple-negative breast cancer (TNBC) patients with metastasis, causes poor survival outcomes. Growing evidence has characterized miRNAs involving in breast cancer brain metastasis; however, currently, there is a lack of prognostic plasma-based indicator for brain metastasis. In this study, high level of miR-211 can act as brain metastatic prognostic marker in vivo. High miR-211 drives early and specific brain colonization through enhancing trans-blood–brain barrier (BBB) migration, BBB adherence, and stemness properties of tumor cells and causes poor survival in vivo. SOX11 and NGN2 are the downstream targets of miR-211 and negatively regulate miR-211-mediated TNBC brain metastasis in vitro and in vivo. Most importantly, high miR-211 is correlated with poor survival and brain metastasis in TNBC patients. Our findings suggest that miR-211 may be used as an indicator for TNBC brain metastasis.

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PITX2 DNA-Methylation: Predictive versus Prognostic Value for Anthracycline-Based Chemotherapy in Triple-Negative Breast Cancer Patients

Breast Care ◽

10.1159/000510468 ◽

2020 ◽

pp. 1-9

Author(s):

Rudolf Napieralski ◽

Gabriele Schricker ◽

Gert Auer ◽

Michaela Aubele ◽

Jonathan Perkins ◽

...

Keyword(s):

Breast Cancer ◽

Dna Methylation ◽

Cancer Patients ◽

Triple Negative Breast Cancer ◽

Predictive Value ◽

Untreated Patient ◽

Triple Negative ◽

Statistical Significance ◽

Breast Cancer Patients ◽

The Impact

Background: PITX2 DNA methylation has been shown to predict outcomes in high-risk breast cancer patients after anthracycline-based chemotherapy. To determine its prognostic versus predictive value, the impact of PITX2 DNA methylation on outcomes was studied in an untreated cohort vs. an anthracycline-treated triple-negative breast cancer (TNBC) cohort. Material and Methods: The percent DNA methylation ratio (PMR) of paired-like homeodomain transcription factor 2 (PITX2) was determined by a validated methylation-specific real-time PCR test. Patient samples of routinely collected archived formalin-fixed paraffin-embedded (FFPE) tissue and clinical data from 144 TNBC patients of 2 independent cohorts (i.e., 66 untreated patients and 78 patients treated with anthracycline-based chemotherapy) were analyzed. Results: The risk of 5- and 10-year overall survival (OS) increased continuously with rising PITX2 DNA methylation in the anthracycline-treated population, but it increased only slightly during 10-year follow-up time in the untreated patient population. PITX2 DNA methylation with a PMR cutoff of 2 did not show significance for poor vs. good outcomes (OS) in the untreated patient cohort (HR = 1.55; p = 0.259). In contrast, the PITX2 PMR cutoff of 2 identified patients with poor (PMR >2) vs. good (PMR ≤2) outcomes (OS) with statistical significance in the anthracycline-treated cohort (HR = 3.96; p = 0.011). The results in the subgroup of patients who did receive anthracyclines only (no taxanes) confirmed this finding (HR = 5.71; p = 0.014). Conclusion: In this hypothesis-generating study PITX2 DNA methylation demonstrated predominantly predictive value in anthracycline treatment in TNBC patients. The risk of poor outcome (OS) correlates with increasing PITX2 DNA methylation.

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Distinct MR Imaging Features of Triple-Negative Breast Cancer with Brain Metastasis

Journal of Neuroimaging ◽

10.1111/jon.12149 ◽

2014 ◽

Vol 25 (3) ◽

pp. 474-481 ◽

Cited By ~ 10

Author(s):

Ren-Hua Yeh ◽

Jyh-Cherng Yu ◽

Chi-Hong Chu ◽

Ching-Liang Ho ◽

Hung-Wen Kao ◽

...

Keyword(s):

Breast Cancer ◽

Brain Metastasis ◽

Mr Imaging ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Imaging Features

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Targeting DNA methylation for treating triple-negative breast cancer

Pharmacogenomics ◽

10.2217/pgs-2019-0078 ◽

2019 ◽

Vol 20 (16) ◽

pp. 1151-1157 ◽

Cited By ~ 3

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.

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Nuclear-Biased DUSP6 Expression is Associated with Cancer Spreading Including Brain Metastasis in Triple-Negative Breast Cancer

International Journal of Molecular Sciences ◽

10.3390/ijms20123080 ◽

2019 ◽

Vol 20 (12) ◽

pp. 3080 ◽

Cited By ~ 4

Author(s):

Fan Wu ◽

Robert D. McCuaig ◽

Christopher R. Sutton ◽

Abel H. Y. Tan ◽

Yoshni Jeelall ◽

...

Keyword(s):

Breast Cancer ◽

Brain Metastasis ◽

Cancer Progression ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Lung Metastases ◽

Her2 Positive ◽

Pathway Gene ◽

Dual Specificity ◽

The Brain

DUSP6 is a dual-specificity phosphatase (DUSP) involved in breast cancer progression, recurrence, and metastasis. DUSP6 is predominantly cytoplasmic in HER2+ primary breast cancer cells, but the expression and subcellular localization of DUSPs, especially DUSP6, in HER2-positive circulating tumor cells (CTCs) is unknown. Here we used the DEPArray system to identify and isolate CTCs from metastatic triple negative breast cancer (TNBC) patients and performed single-cell NanoString analysis to quantify cancer pathway gene expression in HER2-positive and HER2-negative CTC populations. All TNBC patients contained HER2-positive CTCs. HER2-positive CTCs were associated with increased ERK1/ERK2 expression, which are direct DUSP6 targets. DUSP6 protein expression was predominantly nuclear in breast CTCs and the brain metastases but not pleura or lung metastases of TNBC patients. Therefore, nuclear DUSP6 may play a role in the association with cancer spreading in TNBC patients, including brain metastasis.

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