Epigenetic Regulation of Gfi1 in Endocrine-Related Cancers: A Role Regulating Tumor Growth

Prostate and breast cancer constitute the most common cancers among men and women worldwide. The aging population is one of the main risk factors for prostate and breast cancer development and accumulating studies link aging with epigenetic changes. Growth factor independence-1 (Gfi1) is a transcriptional repressor with an important role in human malignancies, including leukemia, colorectal carcinoma, and lung cancer, but its role in prostate and breast cancer is unknown. We have found that Gfi1 epigenetic silencing is a common event in prostate and breast cancer. Gfi1 re-expression in prostate and breast cancer cell lines displaying Gfi1 epigenetic silencing decreases cell proliferation, reduced colony formation density, and tumor growth in nude mice xenografts. In addition, we found that Gfi1 repress alpha 1-anti-trypsin (AAT) and alpha 1-anti-chymotrypsin (ACT) expression, two genes with important functions in cancer development, suggesting that Gfi1 silencing promotes tumor growth by increasing AAT and ACT expression in our system. Finally, Gfi1 epigenetic silencing could be a promising biomarker for prostate cancer progression because it is associated with shorter disease-free survival. In conclusion, our findings strongly indicate that Gfi1 epigenetic silencing in prostate and breast cancer could be a crucial step in the development of these two-well characterized endocrine related tumors.

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Role of GATA3 exon 6 germline mutations in breast cancer progression in Egyptian female patients

Experimental Biology and Medicine ◽

10.1177/1535370220958610 ◽

2020 ◽

pp. 153537022095861

Author(s):

Iman H Ibrahim ◽

Heba G Abdel-Aziz ◽

Fatema EM Hassan ◽

Hesham SA El-Sameea

Keyword(s):

Breast Cancer ◽

Cancer Progression ◽

Disease Free Survival ◽

Germline Mutations ◽

Breast Cancer Progression ◽

Protein Coding ◽

Free Survival ◽

Disease Free ◽

Gata3 Protein

Several mutations act as driver mutations in breast cancer, including GATA3 mutations. Reports of the relation between GATA3 mutations and breast cancer prognosis remain conflicting. Also, the role of GATA3 germline mutations is not well studied. We hypothesize that different mutation types could have different effects. Also, this study aims to assess effect of GATA3 mutations on GATA3 protein function as a transcription factor, and target pathways affected. DNA from de novo breast cancer female patients was sequenced to detect exon 6 GATA3 mutation. Sequence analysis was performed along with clinical and prognostic parameters and disease-free survival. Public datasets were analyzed for differentially expressed genes and pathways with mutant GATA3 patients. Mutations in GATA3 exon 6 were detected in 56.1% of patients (including 2 novel, Lys368fs, Pro354Lys). Intronic mutations were significantly higher in long disease-free survival group, while frameshift mutations were significantly higher in short DFS group. Patients with tumor size ≥20 had significantly higher protein coding and lower intronic mutations compared to patients with tumor size <20 mm. Differential expression and pathway analysis showed that mutant GATA3 had lost its negative regulatory effect on several pathways such as: signaling by interleukins, regulation of TP53 expression, and RUNX3 regulated CDKN1A transcription pathway. PIK3CA, SKP1, FBP1, SMAD3, ANXA9 and CLSTN2 were positively correlated to wild-type GATA3 expression, but not mutant GATA3. Intronic germline mutations of GATA3 could be related to better prognosis, while protein coding GATA3 germline mutations could be related to unfavorable prognosis. GATA3 mutations lead to dysregulation of pathways related to immunity, breast cancer development, and metabolism. Impact statement GATA3 mutations are known to play an important role in breast cancer progression. The exact role and mechanisms of these mutations remain controversial as some studies suggest a relation to breast tumor growth, while others suggest a relation to longer survival. GATA3 germline mutations are not well studied in breast cancer. In this study, it was hypothesized that different types of GATA3 mutations could contribute to the breast cancer progression in different ways. GATA3 exon 6, which is important for GATA3 protein functions, was reported to have hotspots, and hence it was selected for study. Intronic GATA3 germline mutations were found to be related to favorable prognosis, while protein coding mutations were found to be related to unfavorable prognosis. Bioinformatics study of large publically available datasets showed that GATA3 mutations lead to dysregulation of pathways related to T-cells activation, inflammation, and breast cancer development.

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TTK Predicts Triple Positive Breast Cancer Prognosis and Regulates Tumor Proliferation and Invasion

10.21203/rs.3.rs-407725/v1 ◽

2021 ◽

Author(s):

Yunhe Gao ◽

Shanshan Qu ◽

Lanqing Cao ◽

Min Yao

Keyword(s):

Breast Cancer ◽

Cancer Progression ◽

Spindle Assembly Checkpoint ◽

Disease Free Survival ◽

Cancer Prognosis ◽

Clinicopathological Parameters ◽

Free Survival ◽

Kaplan Meier ◽

Disease Free ◽

Positive Breast Cancer

Abstract Background: This study was conducted to investigate the expression of the spindle assembly checkpoint kinase tyrosine/threonine kinase (TTK) in triple positive breast cancer (TPBC) and its effect on TPBC cells. Methods: We analyzed the status of TTK in 69 TPBC samples using immunohistochemistry. The correlation between TTK and clinicopathological parameters was analyzed using a chi-squared test. The prognostic value of TTK was evaluated using Kaplan–Meier survival curves. We analyzed the role of TTK in the invasion and proliferation of TPBC cells in vitro and in vivo. Results: The mean age of the 69 patients with TPBC enrolled in this study was 53 years (range: 29–86 years). TTK expression was positively correlated with tumor size (P = 0.034), p53 status (P = 0.023), TNM stage (P = 0.023), and Ki-67 index (P< 0.001). The Kaplan–Meier curves revealed that TTK expression was correlated with poor disease-free survival (P = 0.001) and overall survival (P = 0.050). Multivariate proportional hazard regression analyses showed that TTK and TNM staging were significant independent predictors of disease-free survival (P = 0.007 and P = 0.034, respectively). Additionally, TTK knockdown inhibited the invasion and proliferation of the BT474 TPBC cell line. Conclusions: The findings of the study indicate that TTK overexpression is associated with cancer progression and prognosis in patients with TPBC, whereas TTK knockdown inhibits the invasion and proliferation of TPBC cells. Thus, TTK may serve as a prognostic marker for TPBC.

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Unbiased Lipidomic Profiling of Triple-Negative Breast Cancer Tissues Reveals the Association of Sphingomyelin Levels with Patient Disease-Free Survival

Metabolites ◽

10.3390/metabo8030041 ◽

2018 ◽

Vol 8 (3) ◽

pp. 41 ◽

Cited By ~ 8

Author(s):

Preeti Purwaha ◽

Franklin Gu ◽

Danthasinghe Piyarathna ◽

Theckelnaycke Rajendiran ◽

Anindita Ravindran ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Progression ◽

Triple Negative ◽

Therapeutic Targets ◽

Disease Free Survival ◽

Sphingolipid Metabolism ◽

Free Survival ◽

Cancer Aggressiveness ◽

Novel Biomarkers ◽

Disease Free

The reprogramming of lipid metabolism is a hallmark of many cancers that has been shown to promote breast cancer progression. While several lipid signatures associated with breast cancer aggressiveness have been identified, a comprehensive lipidomic analysis specifically targeting the triple-negative subtype of breast cancer (TNBC) may be required to identify novel biomarkers and therapeutic targets for this most aggressive subtype of breast cancer that still lacks effective therapies. In this current study, our global LC-MS-based lipidomics platform was able to measure 684 named lipids across 15 lipid classes in 70 TNBC tumors. Multivariate survival analysis found that higher levels of sphingomyelins were significantly associated with better disease-free survival in TNBC patients. Furthermore, analysis of publicly available gene expression datasets identified that decreased production of ceramides and increased accumulation of sphingoid base intermediates by metabolic enzymes were associated with better survival outcomes in TNBC patients. Our LC-MS lipidomics profiling of TNBC tumors has, for the first time, identified sphingomyelins as a potential prognostic marker and implicated enzymes involved in sphingolipid metabolism as candidate therapeutic targets that warrant further investigation.

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P1-06-15: A Genomic Predictor Developed from Breast Cancer Cell Lines Predicts Both Disease-Free Survival and Overall Survival in Breast Cancer Patients Treated with Doxorubicin and Cyclophosphamide: A Collaborative Project of the NSABP and Precision Therapeutics.

10.1158/0008-5472.sabcs11-p1-06-15 ◽

2011 ◽

Author(s):

K Shen ◽

G Tang ◽

C Kim ◽

K Pogue-Geile ◽

SJ Anderson ◽

...

Keyword(s):

Breast Cancer ◽

Overall Survival ◽

Cancer Patients ◽

Disease Free Survival ◽

Breast Cancer Cell Lines ◽

Breast Cancer Patients ◽

Collaborative Project ◽

Free Survival ◽

Disease Free ◽

Precision Therapeutics

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Trastuzumab/Chemo Improves Disease-Free Survival in Early-Stage Breast Cancer

PsycEXTRA Dataset ◽

10.1037/e315042005-001 ◽

2005 ◽

Author(s):

Keyword(s):

Breast Cancer ◽

Early Stage ◽

Disease Free Survival ◽

Early Stage Breast Cancer ◽

Free Survival ◽

Disease Free

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A Novel Automated Immunoassay Platform to Evaluate the Association of Adiponectin and Leptin Levels with Breast Cancer Risk

Cancers ◽

10.3390/cancers13133303 ◽

2021 ◽

Vol 13 (13) ◽

pp. 3303

Author(s):

Debora Macis ◽

Valentina Aristarco ◽

Harriet Johansson ◽

Aliana Guerrieri-Gonzaga ◽

Sara Raimondi ◽

...

Keyword(s):

Breast Cancer ◽

Breast Cancer Risk ◽

Cancer Risk ◽

Cox Model ◽

Disease Free Survival ◽

Postmenopausal Breast Cancer ◽

Enzyme Linked Immunosorbent Assay ◽

Baseline Serum ◽

Free Survival ◽

Disease Free

Adiponectin and leptin are adipokines secreted by the adipose tissue that are associated with several chronic diseases including cancer. We aimed to compare the immunoassay platform ELLA with an enzyme-linked immunosorbent assay (ELISA) kit and to assess whether the results of the association analyses with breast cancer risk were dependent on the assay used. We measured adiponectin and leptin with ELLA and ELISA on baseline serum samples of 116 Italian postmenopausal women enrolled in two international breast cancer prevention trials. Results were compared with Deming, Passing–Bablok regression and Bland–Altman plots. Disease-free survival was analyzed with the Cox model. There was a good correlation between the methods for adiponectin and leptin (r > 0.96). We found an increased breast cancer risk for very low adiponectin levels (HR for ELLA = 3.75; 95% CI: 1.37;10.25, p = 0.01), whereas no significant association was found for leptin levels. The disease-free survival curves were almost identical for values obtained with the two methods, for both biomarkers. The ELLA platform showed a good concordance with ELISA for adiponectin and leptin measurements. Our results support the association of very low adiponectin levels with postmenopausal breast cancer risk, irrespective of the method used. The ELLA platform is a time-saving system with high reproducibility, therefore we recommend its use for biomarker assessment.

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The role of functional polymorphisms in oxidative stress-related genes on early-stage breast cancer survival

The International Journal of Biological Markers ◽

10.1177/17246008211011177 ◽

2021 ◽

pp. 172460082110111

Author(s):

Erika Korobeinikova ◽

Rasa Ugenskiene ◽

Ruta Insodaite ◽

Viktoras Rudzianskas ◽

Jurgita Gudaitiene ◽

...

Keyword(s):

Breast Cancer ◽

Overall Survival ◽

Single Nucleotide Polymorphisms ◽

Early Stage ◽

Disease Free Survival ◽

Early Stage Breast Cancer ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Free Survival ◽

Disease Free

Background: Genetic variations in oxidative stress-related genes may alter the coded protein level and impact the pathogenesis of breast cancer. Methods: The current study investigated the associations of functional single nucleotide polymorphisms in the NFE2L2, HMOX1, P21, TXNRD2, and ATF3 genes with the early-stage breast cancer clinicopathological characteristics and disease-free survival, metastasis-free survival, and overall survival. A total of 202 Eastern European (Lithuanian) women with primary I–II stage breast cancer were involved. Genotyping of the single nucleotide polymorphisms was performed using TaqMan single nucleotide polymorphisms genotyping assays. Results: The CA+AA genotypes of P21 rs1801270 were significantly less frequent in patients with lymph node metastasis and larger tumor size ( P=0.041 and P=0.022, respectively). The TT genotype in ATF3 rs3125289 had significantly lower risk of estrogen receptor (ER), progesterone receptor (PR) negative, and human epidermal growth factor receptor 2 (HER2) positive status ( P=0.023, P=0.046, and P=0.040, respectively). In both, univariate and multivariate Cox analysis, TXNRD2 rs1139793 GG genotype vs. GA+AA was a negative prognostic factor for disease-free survival (multivariate hazard ratio (HR) 2.248; P=0.025) and overall survival (multivariate HR 2.248; P=0.029). The ATF3 rs11119982 CC genotype in the genotype model was a negative prognostic factor for disease-free survival (multivariate HR 5.878; P=0.006), metastasis-free survival (multivariate HR 4.759; P=0.018), and overall survival (multivariate HR 3.280; P=0.048). Conclusion: Our findings suggest that P21 rs1801270 is associated with lymph node metastasis and larger tumor size, and ATF3 rs3125289 is associated with ER, PR, and HER2 status. Two potential, novel, early-stage breast cancer survival biomarkers, TXNRD2 rs1139793 and ATF3 rs11119982, were detected. Further investigations are needed to confirm the results of the current study.

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