Loss of c-KIT expression in breast cancer correlates with malignant transformation of breast epithelium and is mediated by KIT gene promoter DNA hypermethylation

Abstract PurposeThe aim of this study was to explore the diagnostic potential of a panel of five hypermethylated gene promoters in bladder cancer. Individuals with primary BCa and control individuals matching the gender, age and smoking status of the cancer patients were recruited. DNA methylation was assessed for the gene promoters of RASSF1, RARβ, DAPK, hTERT and APC in urine samples collected by spontaneous urination. Fifty patients and 35 healthy controls were recruited, with average age of 70.26 years and average smoking status of 44.78 pack-years. In the BCa group, DNA methylation was detected in 27(61.4%) samples. RASSF1 was methylated in 52.2% of samples. Only 3(13.6%) samples from the control group were methylated, all in the RASSF1 gene promoter. The specificity and sensitivity of this panel of genes to diagnose BCa was 86% and 61% respectively. The RASSF1 gene could diagnose BCa with specificity 86.4% and sensitivity 52.3%. Promoter DNA methylation of this panel of five genes could be further investigated as urine biomarker for the diagnosis of BCa. The RASSF1 could be a single candidate biomarker for predicting BCa patients versus controls. Studies are required in order to develop a geographically adjusted diagnostic biomarker for BCa.Trial registration: ACTRN12620000258954

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Transgelin gene is frequently downregulated by promoter DNA hypermethylation in breast cancer

Clinical Epigenetics ◽

10.1186/s13148-015-0138-5 ◽

2015 ◽

Vol 7 (1) ◽

Cited By ~ 18

Author(s):

Nilufer Sayar ◽

Gurbet Karahan ◽

Ozlen Konu ◽

Betul Bozkurt ◽

Onder Bozdogan ◽

...

Keyword(s):

Breast Cancer ◽

Dna Hypermethylation ◽

Promoter Dna

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Prognostic Significance of Promoter DNA Hypermethylation of cysteine dioxygenase 1 (CDO1) Gene in Primary Breast Cancer

PLoS ONE ◽

10.1371/journal.pone.0144862 ◽

2016 ◽

Vol 11 (1) ◽

pp. e0144862 ◽

Cited By ~ 18

Author(s):

Naoko Minatani ◽

Mina Waraya ◽

Keishi Yamashita ◽

Mariko Kikuchi ◽

Hideki Ushiku ◽

...

Keyword(s):

Breast Cancer ◽

Primary Breast Cancer ◽

Prognostic Significance ◽

Cysteine Dioxygenase ◽

Dna Hypermethylation ◽

Promoter Dna

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DNA Hypermethylation Patterns Detected in Serum as a Tool for Early Breast Cancer Diagnosis

10.21236/ada476292 ◽

2007 ◽

Author(s):

Jennifer Brooks

Keyword(s):

Breast Cancer ◽

Early Breast Cancer ◽

Cancer Diagnosis ◽

Breast Cancer Diagnosis ◽

Dna Hypermethylation

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Allele Imbalance or Loss of Heterozygosity, in Normal Appearing Breast Epithelium as a Novel Biomarker to Predict Future Breast Cancer

10.21236/ada544525 ◽

2011 ◽

Author(s):

Carol L. Rosenberg

Keyword(s):

Breast Cancer ◽

Loss Of Heterozygosity ◽

Breast Epithelium ◽

Allele Imbalance

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Mutation Mechanisms of Breast Cancer among the Female Population in China

Current Bioinformatics ◽

10.2174/1574893615666191220141548 ◽

2020 ◽

Vol 15 (3) ◽

pp. 253-259

Author(s):

Asmaa Amer ◽

Ahmed Nagah ◽

Tianhai Tian ◽

Xinan Zhang

Keyword(s):

Breast Cancer ◽

Gene Mutations ◽

Driver Mutations ◽

Human Breast ◽

Breast Epithelium ◽

Female Population ◽

Multistage Model ◽

The Usa ◽

Intermediate Cells ◽

Mutation Mechanisms

Background: Cancer is a genetic disease caused by the accumulation of gene mutations. It is important to derive the number of driver mutations that are needed for the development of human breast cancer, which may provide insights into the tumor diagnosis and therapy. Objective: This work is designed to investigate whether there is any difference for the mutation mechanism of breast cancer between the patients in the USA and those in China. We study the mechanisms of breast cancer development in China, and then compare these mechanisms with those in the USA. Methods: This work designed a multistage model including both gene mutation and clonal expansion of intermediate cells to fit the dataset of breast cancer in China from 2004 to 2009. Results: Our simulation results show that the maximum number of driver mutations for breast epithelium stem cells of females in China is 13 which is less than the 14 driver mutations of females in the USA. In addition, the two-hit model is the optimal one for the tumorigenesis of females in China, which is also different from the three-hit model that was predicted as the optimal model for the tumorigenesis of females in the USA. Conclusion: The differences of the mutation mechanisms between China and the USA reflect a variety of lifestyle, genetic influences, environmental exposure, and the availability of mammography screening.

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Fatty Acid Synthase Confers Tamoxifen Resistance to ER+/HER2+ Breast Cancer

Cancers ◽

10.3390/cancers13051132 ◽

2021 ◽

Vol 13 (5) ◽

pp. 1132

Author(s):

Javier A. Menendez ◽

Adriana Papadimitropoulou ◽

Travis Vander Steen ◽

Elisabet Cuyàs ◽

Bharvi P. Oza-Gajera ◽

...

Keyword(s):

Breast Cancer ◽

Fatty Acid ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Promoter Activity ◽

Fatty Acid Synthase ◽

Endocrine Resistance ◽

Gene Promoter ◽

Her2 Positive ◽

Her2 Breast Cancer

The identification of clinically important molecular mechanisms driving endocrine resistance is a priority in estrogen receptor-positive (ER+) breast cancer. Although both genomic and non-genomic cross-talk between the ER and growth factor receptors such as human epidermal growth factor receptor 2 (HER2) has frequently been associated with both experimental and clinical endocrine therapy resistance, combined targeting of ER and HER2 has failed to improve overall survival in endocrine non-responsive disease. Herein, we questioned the role of fatty acid synthase (FASN), a lipogenic enzyme linked to HER2-driven breast cancer aggressiveness, in the development and maintenance of hormone-independent growth and resistance to anti-estrogens in ER/HER2-positive (ER+/HER2+) breast cancer. The stimulatory effects of estradiol on FASN gene promoter activity and protein expression were blunted by anti-estrogens in endocrine-responsive breast cancer cells. Conversely, an AKT/MAPK-related constitutive hyperactivation of FASN gene promoter activity was unaltered in response to estradiol in non-endocrine responsive ER+/HER2+ breast cancer cells, and could be further enhanced by tamoxifen. Pharmacological blockade with structurally and mechanistically unrelated FASN inhibitors fully impeded the strong stimulatory activity of tamoxifen on the soft-agar colony forming capacity—an in vitro metric of tumorigenicity—of ER+/HER2+ breast cancer cells. In vivo treatment with a FASN inhibitor completely prevented the agonistic tumor-promoting activity of tamoxifen and fully restored its estrogen antagonist properties against ER/HER2-positive xenograft tumors in mice. Functional cancer proteomic data from The Cancer Proteome Atlas (TCPA) revealed that the ER+/HER2+ subtype was the highest FASN protein expressor compared to basal-like, HER2-enriched, and ER+/HER2-negative breast cancer groups. FASN is a biological determinant of HER2-driven endocrine resistance in ER+ breast cancer. Next-generation, clinical-grade FASN inhibitors may be therapeutically relevant to countering resistance to tamoxifen in FASN-overexpressing ER+/HER2+ breast carcinomas.

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Integrin α3β1 Promotes Invasive and Metastatic Properties of Breast Cancer Cells through Induction of the Brn-2 Transcription Factor

Cancers ◽

10.3390/cancers13030480 ◽

2021 ◽

Vol 13 (3) ◽

pp. 480

Author(s):

Rakshitha Pandulal Miskin ◽

Janine S. A. Warren ◽

Abibatou Ndoye ◽

Lei Wu ◽

John M. Lamar ◽

...

Keyword(s):

Breast Cancer ◽

Transcription Factor ◽

Cancer Cells ◽

Cell Invasion ◽

Breast Cancer Cells ◽

Gene Promoter ◽

Akt Inhibitor ◽

Integrin Α3β1

In the current study, we demonstrate that integrin α3β1 promotes invasive and metastatic traits of triple-negative breast cancer (TNBC) cells through induction of the transcription factor, Brain-2 (Brn-2). We show that RNAi-mediated suppression of α3β1 in MDA-MB-231 cells caused reduced expression of Brn-2 mRNA and protein and reduced activity of the BRN2 gene promoter. In addition, RNAi-targeting of Brn-2 in MDA-MB-231 cells decreased invasion in vitro and lung colonization in vivo, and exogenous Brn-2 expression partially restored invasion to cells in which α3β1 was suppressed. α3β1 promoted phosphorylation of Akt in MDA-MB-231 cells, and treatment of these cells with a pharmacological Akt inhibitor (MK-2206) reduced both Brn-2 expression and cell invasion, indicating that α3β1-Akt signaling contributes to Brn-2 induction. Analysis of RNAseq data from patients with invasive breast carcinoma revealed that high BRN2 expression correlates with poor survival. Moreover, high BRN2 expression positively correlates with high ITGA3 expression in basal-like breast cancer, which is consistent with our experimental findings that α3β1 induces Brn-2 in TNBC cells. Together, our study demonstrates a pro-invasive/pro-metastatic role for Brn-2 in breast cancer cells and identifies a role for integrin α3β1 in regulating Brn-2 expression, thereby revealing a novel mechanism of integrin-dependent breast cancer cell invasion.

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