Id4 Regulates Mammary Epithelial Cell Growth and Differentiation and Is Overexpressed in Rat Mammary Gland Carcinomas

Shan, Liang; Yu, Minshu; Qiu, Cunping; Snyderwine, Elizabeth G.

doi:10.1016/s0002-9440(10)63604-8

Cited by 35 publications

(51 citation statements)

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“…Others have found nuclear expression of Id-4 to be increased in the initiation and progression of breast cancer in rat. 24 Id-4 has been shown to positively correlate with invasion ability of a mouse breast cancer cell line in that same study. A significant association between Id-4 promoter hypermethylation and nodal metastasis in human breast cancer samples has been found.…”

Section: Discussionmentioning

confidence: 73%

“…22 Id-4 expressions were shown to correlate with invasiveness of breast cancer cells 23 and breast carcinomas in mice. 24 However, another study has suggested that hypermethylation of Id-4, which leads to reduced gene expression, is significantly associated with node-positive T1 primary breast cancer. 25 These findings show that Id proteins may also be involved in metastasis of different types of cancer.…”

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confidence: 99%

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Id proteins expression in prostate cancer: high-level expression of Id-4 in primary prostate cancer is associated with development of metastases

et al. 2006

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A major cause of treatment failure for prostate cancer is the development of androgen-independent metastatic disease. Id protein family, a group of basic helix-loop-helix transcription factors, has been shown to be involved in carcinogenesis and a prognostic marker in several types of human cancers. In this study, we examined the expressions of four Id proteins, Id-1, -2, -3 and -4, in 125 clinical prostate cancer specimens as well as 40 nodular hyperplasia specimens by immunohistochemistry. The expressions of Id proteins were correlated with Gleason grading and metastatic progress of the tumors. We found that Id proteins were dysregulated in prostate cancer. Id-1 and -2 expressions were elevated while Id-3 and -4 expressions were reduced in prostate cancers compared to nodular hyperplasia. Cytoplasmic staining of Id-1 (P ¼ 0.013) and nuclear staining of Id-2 (P ¼ 0.001) and Id-4 (Po0.001) were positively correlated with Gleason score. The results indicate that these Id proteins may play a positive role in the development of prostate cancer. In contrast, Id-3 might have an inverse relationship with prostate neoplastic transformation (P ¼ 0.002) and cancer progression (P ¼ 0.022). We found that Id-4 nuclear overexpression in the primary prostate cancers significantly increased the risks to the development of metastasis in the patients (odds ratio ¼ 3.215, 95% confidence interval ¼ 1.150-8.987, P ¼ 0.026). Our results suggest that in prostate cancer patients, differential Id proteins expressions may be a useful marker for poor prognosis, and Id-4 may be a potential prognostic marker for distant metastasis.

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Section: Discussionmentioning

confidence: 73%

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confidence: 99%

Id proteins expression in prostate cancer: high-level expression of Id-4 in primary prostate cancer is associated with development of metastases

et al. 2006

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“…ID family members including ID1, ID2, and ID3 have identified functions in tumor progression, including angiogenesis, invasion, and metastasis (Lyden et al, 1999;Benezra, 2001;Benezra et al, 2001;Folkman, 2002;Ruzinova and Benezra, 2003;, and in other circumstances ID1 and ID2 may function as tumor suppressors in rodents (Itahana et al, 2003;Sikder et al, 2003;Russell et al, 2004). The function of ID4 in tumorigenesis is similarly complex (Beger et al, 2001;Bellido et al, 2003;Chan et al, 2003;Shan et al, 2003;Umetani et al, 2004Umetani et al, , 2005 Jeon et al, 2008). ID4 seems to function as a tumor suppressor in a variety of cancers (Chan et al, 2003;Umetani et al, 2004Umetani et al, , 2005Yu et al, 2005) and is downregulated by promoter hypermethylation in several tumor types (Chan et al, 2003;Umetani et al, 2004Umetani et al, , 2005Yu et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Inhibitor of DNA binding-4 promotes angiogenesis and growth of glioblastoma multiforme by elevating matrix GLA levels

et al. 2010

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Inhibitor of differentiation-4 is highly expressed in glioblastoma multiforme (GBM). We report a novel proangiogenic function for inhibitor of differentiation-4 in the growth of glioblastoma xenografts. Tumor-derived cell cultures expressing elevated levels of ID4 produced enlarged xenografts in immunosuppressed mice that were better vascularized than corresponding control tumors and expressed elevated matrix GLA protein (MGP) that mediated enhanced tumor angiogenesis. Inhibition of MGP resulted in smaller and less vascularized xenografts. Our finding shows a novel function for ID4 in tumor angiogenesis, and identifies ID4 and MGP as possible therapeutic targets for GBM.

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“…[28][29][30] The study of ID4 expression in breast cancers has also lead to conflicting results. The expression of rat Id4 was examined in rat induced mammary gland tumors by Shan et al 31 By real-time polymerase chain reaction analysis, relative expression of ID4 mRNA in carcinomas, adenomas and normal tissue was 27, 6 and 1, respectively. Immunohistochemical analysis indicated statistically significant elevated nuclear expression for Id4 protein in carcinomas compared to adenomas and normal mammary gland.…”

Section: Introductionmentioning

confidence: 99%

“…The authors conclude that these results implicate Id4 in rat mammary gland carcinogenesis and suggest that Id4 may contribute to carcinogenesis by inhibiting mammary epithelial cell differentiation and stimulating mammary epithelial cell growth. 31 More recently, Umetani et al assessed the methylation status of ID4 promoter CpG island by methylation-specific PCR (MSP) and ID4 mRNA level by quantitative real-time RT-PCR. Of the eight cell lines studied, ID4 mRNA level was suppressed in two fully methylated cell lines.…”

Section: Introductionmentioning

confidence: 99%

Tumoral expression of BRCA1, Estrogen receptor alpha and ID4 protein in patients with sporadic breast cancer

Roldán¹,

Delgado²,

Musé³

2006

Cancer Biology & Therapy

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Introduction: BRCA1 expression is downregulated in a third of sporadic breast cancers (SBC). Most of the tumors in which BRCA1 function is diminished do not express estrogen receptor alpha (ER). Recent studies suggest that the inhibitor of DNA binding (ID)-4 could participate in the hormonal regulation of BRCA1 expression.Objective: To study the relationship between tumoral expression of BRCA1, ER and ID4 in SBCs.Patients and methods: Forty patients with pathologic confirmation of SBC were included in this study. The mRNA expression of BRCA1, ER and ID4, determined by reverse transcription and polymerase chain reaction (RT-PCR), was correlated with the expression of gliceraldehid-3-phosphate-dehydrogenase (GAPDH). The results were analyzed using two-sided nonparametric tests (Chi-square and Spearman's rank correlation test) with α < 0.05.Results: Most of the tumors that expressed BRCA1 mRNA were ER-positive (p < 0.0001). In addition, a positive correlation was observed between the level of expression of these mRNAs (rs = 0.75 95% CI = 0.57-0.86; p < 0.0001). An inverse association was observed between the mRNA expression of BRCA1 and ID4 (p = 0.024) and a negative correlation between their levels of expression (rs = -0.35 95% CI -0.59 a -0.04; p = 0.028). Moreover, a negative correlation was stated between the level mRNAs of ER and ID4 (rs = -0.45 95% CI -0.66 a -0.16; p = 0.0039).Discussion: In this study we demonstrate an association between the tumoral expression of BRCA1, ER and ID4 in patients with SBC. These results are in concordance with previous studies, however, to our knowledge, no other reports have described a relationship between the expression of ID4 and ER at the mRNA level in human breast cancers. These results suggest that ID4 participates in the molecular events that regulate BRCA1 and ER expression, suggesting its role as a tumor marker or potential therapeutic target.

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Id4 Regulates Mammary Epithelial Cell Growth and Differentiation and Is Overexpressed in Rat Mammary Gland Carcinomas

Abstract: Id4 belongs to a family of helix-loop-helix (HLH) proteins that impact cellular growth and differentiation via regulation of basic HLH transcription factors. Herein the rat

Cited by 35 publications

References 38 publications

Id proteins expression in prostate cancer: high-level expression of Id-4 in primary prostate cancer is associated with development of metastases

Id proteins expression in prostate cancer: high-level expression of Id-4 in primary prostate cancer is associated with development of metastases

Inhibitor of DNA binding-4 promotes angiogenesis and growth of glioblastoma multiforme by elevating matrix GLA levels

Tumoral expression of BRCA1, Estrogen receptor alpha and ID4 protein in patients with sporadic breast cancer

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