Estrogen receptor-α promoter methylation is a biomarker for outcome prediction of cisplatin resistance in triple-negative breast cancer

Xu, Junnan; Sun, Tao; Guo, Xiangyu; Wang, Yan; Jing, Mingxi

doi:10.3892/ol.2017.7637

Cited by 8 publications

(8 citation statements)

References 53 publications

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“…Shaw et al (23) demonstrated that the level of TMB calculated by total circulating free DNA and the circulating tumor cell count (≥5) were both significantly associated with overall survival in patients with metastatic BC, unlike the cancer-associated biomarkers, including cancer antigen 15-3 and alkaline phosphatase (23,24). The similar trend of estrogen receptor 1 and KRAS proto-oncogene, GTPase gene mutations was absent from primary tumor tissue, and appeared to be acquired with disease progression (23,25). This TMB marker may reflect the degree of metastatic burden and may serve as a favorable predictor for clinical decision-making.…”

Section: Discussionmentioning

confidence: 83%

Elevated tumor mutation burden and immunogenic activity in patients with hormone receptor‑negative or human epidermal growth factor receptor 2‑positive breast cancer

Bao²,

Wu³

et al. 2019

Oncol Lett

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Immunotherapy has been found to be efficient in a variety of cancers and, therefore, may be a promising strategy for breast cancer (BC), particularly due to the limited therapeutic options currently available for triple-negative BC (TNBC). However, heterogeneity of tumor mutation burden (TMB), immune gene expression and mismatch repair (MMR) gene activity across BC subtypes has not been well characterized. In the present study, a comprehensive analysis of TMB, expression levels of immune cell type marker genes, and expression levels of MMR-associated genes was performed. A total of 5 MMR-associated genes, including MLH1, MLH3, MSH2, MSH6 and PMS2 , were analyzed. Patients that harbored at least two MMR genes with expression levels in the lower 10% percentile across the cohort were considered as potentially aberrant (lost expression). Hormone receptor (HR)-negative BC is associated with a higher TMB and immune gene expression compared with HR-positive BC [TMB, estrogen receptor (ER)-negative vs. ER-negative, 55 vs. 32, respectively; P=4.1×10 −13 ; progesterone receptor (PR)-negative vs. PR-positive, 53 vs. 31, respectively; P<2.2×10 −16 ]. By contrast, human epidermal growth factor receptor 2 (HER2)-negative BC tended to have a lower TMB and decreased immune gene expression compared with HER2-positive BC (TMB, HER2-negative vs. HER2-positive, 36 vs. 48, respectively; P=0.02). Furthermore, aberrant expression of MMR genes was found to be more common in HR-negative compared with HR-positive BC (P<0.001). Significantly higher expression levels of each immune marker gene of four major immune cell types were found in patients who were HR-negative compared with patients who were HR-positive (P<0.001). The findings of the present study suggest that HR-negative or HER2-positive BC exhibits elevated TMB and immunogenic activity, and immunotherapeutic options are recommended.

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Section: Discussionmentioning

confidence: 83%

Elevated tumor mutation burden and immunogenic activity in patients with hormone receptor‑negative or human epidermal growth factor receptor 2‑positive breast cancer

Bao²,

Wu³

et al. 2019

Oncol Lett

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“…Dysregulation of ERα is often associated with advanced breast cancers by altering the ERα-dependent genes that are involved in cell proliferation and metastasis. The loss of ESR1 expression in TNBC is a result of the hypermethylation of specific CpG islands within the ESR1 promoter through regulation of DNA methyltransferase (DNMT) 7,8 . Furthermore, ERα re-expression by 5-aza-dC, a DNMT inhibitor, was shown to inhibit tumor growth of TNBC cells in vitro and in vivo, indicating that its expression can be modulated by epigenetic mechanisms and restore the sensitivity of TNBC to endocrine therapy 9 .…”

Section: Introductionmentioning

confidence: 99%

RNF208, an estrogen-inducible E3 ligase, targets soluble Vimentin to suppress metastasis in triple-negative breast cancers

et al. 2019

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The development of triple-negative breast cancer (TNBC) negatively impacts both quality of life and survival in a high percentage of patients. Here, we show that RING finger protein 208 (RNF208) decreases the stability of soluble Vimentin protein through a polyubiquitin-mediated proteasomal degradation pathway, thereby suppressing metastasis of TNBC cells. RNF208 was significantly lower in TNBC than the luminal type, and low expression of RNF208 was strongly associated with poor clinical outcomes. Furthermore, RNF208 was induced by 17β-estradiol (E2) treatment in an estrogen receptor alpha (ΕRα)-dependent manner. Overexpression of RNF208 suppresses tumor formation and lung metastasis of TNBC cells. Mechanistically, RNF208 specifically polyubiquitinated the Lys97 residue within the head domain of Vimentin through interaction with the Ser39 residue of phosphorylated Vimentin, which exists as a soluble form, eventually facilitating proteasomal degradation of Vimentin. Collectively, our findings define RNF208 as a negative regulator of soluble Vimentin and a prognostic biomarker for TNBC cells.

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“…Another relevant issue is the estimation of tumor cell density in tissue samples tested. For example, the percentage of tumor in tissue sections chosen for DNA purification varies widely among published reports, from >30% of tumor cells [ 117 ] to >70% [ 82 , 125 ] or even >90% [ 98 , 122 ]. This variability is very likely to influence the determination of methylation levels (even considering that normalization for input has been made), jeopardizing the comparison of results and the reproducibility of experiments, undermining the possibility of biomarker validation [ 138 ].…”

Section: Discussionmentioning

confidence: 99%

DNA Methylation Biomarkers for Prediction of Response to Platinum-Based Chemotherapy: Where Do We Stand?

Tavares

Gumauskaitė

Lobo

et al. 2022

Cancers

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Platinum-based chemotherapy is routinely used for the treatment of several cancers. Despite all the advances made in cancer research regarding this therapy and its mechanisms of action, tumor resistance remains a major concern, limiting its effectiveness. DNA methylation-based biomarkers may assist in the selection of patients that may benefit (or not) from this type of treatment and provide new targets to circumvent platinum chemoresistance, namely, through demethylating agents. We performed a systematic search of studies on biomarkers that might be predictive of platinum-based chemotherapy resistance, including in vitro and in vivo pre-clinical models and clinical studies using patient samples. DNA methylation biomarkers predictive of response to platinum remain mostly unexplored but seem promising in assisting clinicians in the generation of more personalized follow-up and treatment strategies. Improved methodologies for their detection and quantification, including non-invasively in liquid biopsies, are additional attractive features that can bring these biomarkers into clinical practice, fostering precision medicine.

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Estrogen receptor-α promoter methylation is a biomarker for outcome prediction of cisplatin resistance in triple-negative breast cancer

Cited by 8 publications

References 53 publications

Elevated tumor mutation burden and immunogenic activity in patients with hormone receptor‑negative or human epidermal growth factor receptor 2‑positive breast cancer

Elevated tumor mutation burden and immunogenic activity in patients with hormone receptor‑negative or human epidermal growth factor receptor 2‑positive breast cancer

RNF208, an estrogen-inducible E3 ligase, targets soluble Vimentin to suppress metastasis in triple-negative breast cancers

DNA Methylation Biomarkers for Prediction of Response to Platinum-Based Chemotherapy: Where Do We Stand?

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