Breast Cancer Tumor Suppressors: A Special Emphasis on Novel Protein Nischarin

Maziveyi, Mazvita; Alahari, Suresh K.

doi:10.1158/0008-5472.can-15-1395

Cited by 48 publications

(45 citation statements)

References 37 publications

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“…1,2 Furthermore, more recently published data have demonstrated that Nischarin binds not only to α5 integrin, but also to GTP-loaded Ras-related C3 botulinum toxin substrate 1 (Rac 1), p21 activate kinase1 (PAK1) (a downstream effector of Rac, and cell division control protein 42 (Cdc42)), liver kinase b1 (LKB1) and LIM kinase1 (LIMK1). 3 We have shown that Nischarin blocks PAK-LIMK signaling in vitro. 4 LIMK1 and PAK1 are hyperactive and upregulated in several types of breast cancer, and PAK1 functions as an oncogene.…”

Section: Introductionmentioning

confidence: 83%

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Knockout model reveals the role of Nischarin in mammary gland development, breast tumorigenesis and response to metformin treatment

Dong

Ruiz-Calderon

Rathinam

et al. 2019

Intl Journal of Cancer

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Previously, our lab discovered the protein Nischarin and uncovered its role in regulating cell migration and invasion via its interactions with several proteins. We subsequently described a role for Nischarin in breast cancer, in which it is frequently underexpressed. To characterize Nischarin's role in breast tumorigenesis and mammary gland development more completely, we deleted a critical region of the Nisch gene (exons 7–10) from the mouse genome and observed the effects. Mammary glands in mutant animals showed delayed terminal end bud formation but did not develop breast tumors spontaneously. Therefore, we interbred the animals with transgenic mice expressing the mouse mammary tumor virus‐polyoma middle T‐antigen (MMTV‐PyMT) oncogene. The MMTV‐PyMT mammary glands lacking Nischarin showed increased hyperplasia compared to wild‐type animal tissues. Furthermore, we observed significantly increased tumor growth and metastasis in Nischarin mutant animals. Surprisingly, Nischarin deletion decreased activity of AMPK and subsequently its downstream effectors. Given this finding, we treated these animals with metformin, which enhances AMPK activity. Here, we show for the first time, metformin activates AMPK signaling and inhibits tumor growth of Nischarin lacking PyMT tumors suggesting a potential use for metformin as a cancer therapeutic, particularly in the case of Nischarin‐deficient breast cancers.

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Section: Introductionmentioning

confidence: 83%

“…The tumors were measured by a caliper and the volumes were calculated as described above. When tumors reached size of~100 mm 3 . The mice were randomly distributed into two groups that were untreated or treated by I.P.…”

Section: Metformin Treatment For Pymt Micementioning

confidence: 99%

Knockout model reveals the role of Nischarin in mammary gland development, breast tumorigenesis and response to metformin treatment

Dong

Ruiz-Calderon

Rathinam

et al. 2019

Intl Journal of Cancer

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“…[49] Dedeurwaerder and Fuks et al [50] reported that high expression of some T-cell marker genes was correlated with a better clinical outcome in breast cancer. The Chi-square (and Fisher's exact) test had a notably ( P < .05) higher percentage of promoter methylation of the ESR1 gene in breast cancer patients with triple negative and HER2 phenotypes with poorer prognosis by Martinez-Galan et al [51] Some methylated genes within the promoter (i.e., RASSF1A , RARbeta2 , BRCA1 , and GSTP1 ) have been identified to be associated with poor prognosis of breast cancer patients, [31–33,44] suggesting that aberrantly methylated genes may become potential prognostic factors.…”

Section: Discussionmentioning

confidence: 99%

Prognostic role of methylated GSTP1, p16, ESR1 and PITX2 in patients with breast cancer

Sheng

Guo²,

Yang³

2017

Medicine

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Background:BRCA1 and RASSF1A promoter methylation has been reported to be correlated with a worse survival in patients with breast cancer. However, the prognostic values of GSTP1, p16, ESR1, and PITX2 promoter methylation in breast cancer remain to be determined. Here, we performed this study to evaluate the prognostic significance of GSTP1, p16, ESR1, and PITX2 promoter methylation in breast cancer.Methods:A range of online databases was systematically searched to identify available studies based on the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guideline. The pooled hazard ratios (HRs) with their 95% confidence intervals (95% CIs) were applied to estimate the prognostic effect of GSTP1, p16, ESR1, and PITX2 promoter methylation in breast cancer for multivariate regression analysis.Results:13 eligible articles involving 3915 patients with breast cancer were analyzed in this meta-analysis. In a large patient population, GSTP1 showed a trend toward a worse prognosis in overall survival (OS) (HR = 1.64, 95% CI = 0.93–2.87, P = .085). PITX2 promoter methylation was significantly correlated with a worse prognosis in OS (HR = 1.57, 95% CI = 1.15–2.14, P = .004), but no association between p16 promoter methylation and OS (HR = 0.92, 95% CI = 0.31–2.71, P = .884). PITX2 promoter methylation was significantly correlated with an unfavorable prognosis of patients with breast cancer in metastasis-free survival (MFS) (HR = 1.73, 95% CI = 1.33–2.26, P < .001). The result from 3 studies with 227 cases showed that ESR1 promoter methylation was linked to a worse prognosis in OS (HR = 1.55, 95% CI = 1.06–2.28, P = .025).Conclusions:Our findings suggest ESR1 and PITX2 promoter methylation may be correlated with a worse survival of patients with breast cancer (ESR1: OS, PITX2: OS and MFS). The clinical utility of aberrantly methylated ESR1 and PITX2 could be a promising factor for the prognosis of breast cancer.

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“…Breast cancer is a heterogeneous and hormone-dependent disease and is mainly attributed to the promoter methylation of tumor suppressor genes (TSGs) involving cell proliferation, cell death, cell migration, and cell invasion, all of which lead to the development of this disease [29]. The absence or downregulation of gene expression, which is correlated with CpG islands related to the promoter methylation of different genes, has been shown in many cancers, including breast cancer [30–32].…”

Section: Discussionmentioning

confidence: 99%

Detection of 14-3-3 sigma (σ) promoter methylation as a noninvasive biomarker using blood samples for breast cancer diagnosis

Huang

Ying

et al. 2016

Oncotarget

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As a tumor suppressor gene, 14-3-3 σ has been reported to be frequently methylated in breast cancer. However, the clinical effect of 14-3-3 σ promoter methylation remains to be verified. This study was performed to assess the clinicopathological significance and diagnostic value of 14-3-3 σ promoter methylation in breast cancer. 14-3-3 σ promoter methylation was found to be notably higher in breast cancer than in benign lesions and normal breast tissue samples. We did not observe that 14-3-3 σ promoter methylation was linked to the age status, tumor grade, clinic stage, lymph node status, histological subtype, ER status, PR status, HER2 status, or overall survival of patients with breast cancer. The combined sensitivity, specificity, AUC (area under the curve), positive likelihood ratios (PLR), negative likelihood ratios (NLR), diagnostic odds ratio (DOR), and post-test probability values (if the pretest probability was 30%) of 14-3-3 σ promoter methylation in blood samples of breast cancer patients vs. healthy subjects were 0.69, 0.99, 0.86, 95, 0.31, 302, and 98%, respectively. Our findings suggest that 14-3-3 σ promoter methylation may be associated with the carcinogenesis of breast cancer and that the use of 14-3-3 σ promoter methylation might represent a useful blood-based biomarker for the clinical diagnosis of breast cancer.

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Breast Cancer Tumor Suppressors: A Special Emphasis on Novel Protein Nischarin

Cited by 48 publications

References 37 publications

Knockout model reveals the role of Nischarin in mammary gland development, breast tumorigenesis and response to metformin treatment

Knockout model reveals the role of Nischarin in mammary gland development, breast tumorigenesis and response to metformin treatment

Prognostic role of methylated GSTP1, p16, ESR1 and PITX2 in patients with breast cancer

Detection of 14-3-3 sigma (σ) promoter methylation as a noninvasive biomarker using blood samples for breast cancer diagnosis

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