Loss of Nuclear BRCA1 Expression in Breast Cancers Is Associated with a Highly Proliferative Tumor Phenotype

Jarvis, Elizabeth; Kirk, Judy

doi:10.1016/s0165-4608(97)00267-7

Cited by 51 publications

(39 citation statements)

References 20 publications

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“…41 Furthermore, it has been suggested in 2 independent studies that loss of nuclear BRCA1 expression in breast cancers is associated with highly proliferative tumour phenotypes. 42,43 In light of these commonalities for re-compartmentalisation of TSG function from the nucleus to the cytoplasm, it will be of interest in future studies to determine the regulatory mechanisms that control re-distribution of these TSG or indeed if there are any common mechanisms which may regulate one or more critical pro-proliferative related gene products.…”

Section: Discussionmentioning

confidence: 99%

Differential subcellular localisation of the tumour suppressor protein LIMD1 in breast cancer correlates with patient survival

Spendlove¹,

Al‐Attar²,

Watherstone³

et al. 2008

Intl Journal of Cancer

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The tumour suppressor gene (TSG) LIM domain containing protein 1 (LIMD1) has been associated with transformation of epithelial cells of the lung and its expression is downregulated in all lung tumour samples tested compared to normal lung matched controls. In the first study of its kind we used an anti-LIMD1 specific monoclonal antibody to investigate expression/localisation of the LIMD1 protein in a well-characterised tissue microarray of breast cancers and normal adjacent epithelia. Comparison of tumour with adjacent normal and distant normal tissue demonstrated that LIMD1 expression is moderate to high compared to tumour. There was also a significant correlation with histological grade (p 5 0.0001), tumour size (p 5 0.013) and tumour type (p 5 0.004) indicating an association with aggressive disease. Cytoplasmic LIMD1 expression was seen in 99.3% of cases, with 43.1% showing both nuclear and cytoplasmic localisation. Absence/loss of nuclear staining showed a strong correlation with patient survival and was indicative of poor prognosis (p 5 0.033). There was no association with lymph node status and other clinicopathological parameters. Nuclear staining was more pronounced in better prognosis tumours and normal tissue. This study demonstrates that LIMD1 represents a novel prognostic marker for breast cancer. Combined with the fact that LIMD1 expression is downregulated in lung cancers this clearly indicates that LIMD1 may represent a critical TSG, the function of which is deregulated via overall loss of expression and/or relocalisation within the cell during tumour development. The possible functions of LIMD1 localisation within the nucleus and cytoplasm and its relationship to tumour prognosis are discussed. ' 2008 Wiley-Liss, Inc.Key words: LIMD1; Ajuba; breast cancer; E-cadherin; tissue microarray; prognostic indicator Breast cancer is the most common cause of cancer-related death in women in the western world. Alterations in tumour suppressor genes (TSG) and oncogenes are common causes for the higher proliferative rates and pathogenic characteristics associated with tumour development. Cytogenetics and allelotyping have shown that allelic loss from several distinct regions on chromosome 3p, including 3p25, 3p21-22, 3p21.3, 3p12-13 and 3p14, are the earliest and most frequent genomic abnormalities involved in a wide spectrum of major epithelial cancers of lung 1-6 and breast tissues 7-9 as well as many other epithelial derived cancers. [10][11][12][13] Specifically the 3p21.3 gene cluster contains many TSG and oncogenes and is a region of major loss of heterozygosity in lung cancers. [14][15][16] Abnormalities at the 3p21.3 chromosomal region include homozygous deletions, loss of heterozygosity and expressional deficiencies that can be induced through methylation of promoters, altered mRNA transcripts and loss of protein translocation. 17 The chromosome 3 commonly eliminated region (C3CER1) is located within the 3p21.3 gene cluster. The C3CER1 contains several putative TSG and is eliminated in many forms o...

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Section: Discussionmentioning

confidence: 99%

Differential subcellular localisation of the tumour suppressor protein LIMD1 in breast cancer correlates with patient survival

Spendlove¹,

Al‐Attar²,

Watherstone³

et al. 2008

Intl Journal of Cancer

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“…A growing number of studies have linked the decreased expression of the BRCA1 gene to both the initiation and progression of sporadic breast cancer (Thompson et Jarvis et al, 1998;Ozcelik et al, 1998;Catteau et al, 1999). Characterizing the elements regulating the BRCA1 promoter is a crucial part of understanding how this change in expression occurs at the molecular level.…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, the expression of the BRCA1 gene has been reported to be decreased in a variety of sporadic breast tumors, and appears to be correlated with tumor progression (Thompson et al, 1995). BRCA1 protein levels also decrease in higher grade tumors (Wilson et al, 1999) which may also involve a loss of nuclear BRCA1 staining (Jarvis et al, 1998). Alterations in gene expression may result from preferential allelic expression of the BRCA1 gene (Ozcelik et al, 1998) or from loss of heterozygosity even in sporadic tumors .…”

Section: Introductionmentioning

confidence: 99%

GA-binding protein α/β is a critical regulator of the BRCA1 promoter

et al. 2000

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Decreased expression of BRCA1 may play a role in the etiology of sporadic breast cancer. Deletion and point mutant analysis of proximal promoter elements in the BRCA1 1a promoter revealed a 22 bp region which was critical for the expression of the promoter in MCF-7 cells, but had a much reduced e ect in T47D cells. The main transcription factor interacting with this site was identi®ed as GABPa/b, and a discrete DNA binding complex was only observed in nuclear extracts from MCF-7 cells. Cotransfection experiments with GABPa and b1 expression vectors produced transactivation of this element in both lines. These results suggest that GABPa/b is a critical activator of BRCA1 expression, and that its activity may di er in human breast cell lines.

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“…Caspase 1 is an important regulator of epithelial cell apoptosis and its downregulation has been reported in breast, gastric, colon and prostate cancers (Boudreau et al, 1995;Jarry et al, 1999;Winter et al, 2001;Jee et al, 2005). Loss of BRCA1 is associated with a more aggressive phenotype in sporadic breast cancer (Jarvis et al, 1998;Taylor et al, 1998) and concomitant loss of FHIT and BRCA1 alleles has also been reported in a number of repair-deficient cancers including breast cancer and ovarian cancers (Wilson et al, 1999;Turner et al, 2002;Santos et al, 2004).…”

Section: Upper Row (Hande) Cancer (A and D) Dcis (B) And Hyperplasia mentioning

confidence: 99%

The expression of FHIT, PCNA and EGFR in benign and malignant breast lesions

Terry

Londesborough

et al. 2006

Br J Cancer

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Immunohistochemical staining for FHIT and PCNA proteins was carried out in 451 breast lesions showing nonproliferative benign breast disease (BBD) (n ¼ 263), proliferative BBD without atypia (n ¼ 128), proliferative BBD with atypia (n ¼ 11), carcinoma in situ (n ¼ 15) or invasive carcinoma (n ¼ 34) and for EGFR protein in a subset of 71 of these cases. FHIT underexpression was not detected in nonproliferative lesions, but occurred in 2% of proliferative BBD without atypia, 10% proliferative BBD with atypia, 27% of carcinoma in situ and 41% of invasive carcinoma, which suggests that it could be useful in assessing those carcinoma in situ lesions (ductal, DCIS and lobular, LCIS) that are more likely to progress to malignancy. Preliminary microarray comparisons on DCIS and invasive carcinoma samples dissected from formalin-fixed paraffin sections showed a consistent downregulation of two previously identified FHIT-related genes, caspase 1 and BRCA1 in lesions underexpressing FHIT.

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Loss of Nuclear BRCA1 Expression in Breast Cancers Is Associated with a Highly Proliferative Tumor Phenotype

Cited by 51 publications

References 20 publications

Differential subcellular localisation of the tumour suppressor protein LIMD1 in breast cancer correlates with patient survival

Differential subcellular localisation of the tumour suppressor protein LIMD1 in breast cancer correlates with patient survival

GA-binding protein α/β is a critical regulator of the BRCA1 promoter

The expression of FHIT, PCNA and EGFR in benign and malignant breast lesions

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