Aberrant methylation of the BRCA1 CpG island promoter is associated with decreased BRCA1 mRNA in sporadic breast cancer cells

Rice, Judd C.; Massey-Brown, Kathy; Futscher, Bernard W.

doi:10.1038/sj.onc.1202086

Cited by 220 publications

(165 citation statements)

References 21 publications

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“…Although the mutation rate is very low, the frequency of down regulation of ING1 in tumours is very substantial, similar to those described for BRCA1 (Thompson et al, 1995;Dobrovic and Simpfendorfer, 1997;Magdinier et al, 1998;Rice et al, 1998;Sourvinos and Spandidos, 1998) and p16 INK4A Brenner et al, 1996;Herman et al, 1995).…”

Section: Discussionsupporting

confidence: 64%

Suppression of ING1 expression in sporadic breast cancer

et al. 1999

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Down regulation of the ING1 candidate tumour suppressor promotes growth in soft agar and focus formation in vitro and tumour formation in vivo. ING1 encodes a nuclear, cell cycle-regulated protein, overexpression of which e ciently blocks cell growth and is capable of inducing apoptosis in di erent experimental systems. Here we present the ®rst report of ING1 mutation and expression analysis in a total of 452 cancer samples. One germline missense alteration and three germline silent alterations were detected in 377 primary breast cancers while marked (2 ± 10-fold) decreases in ING1 mRNA expression were seen in 44% of primary breast cancers and in ten of ten breast cancer cell lines examined. Furthermore, the majority of breast cancers (58%) showing decreased ING1 expression had metastasized to regional lymph nodes whereas only 9% of cancers with elevated ING1 expression, compared to adjacent normal tissues, were metastatic. Thus, ING1 mutation is very rare in breast or ovarian cancers, however, repression of ING1 expression frequently accompanies tumour development of breast cancer.

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Section: Discussionsupporting

confidence: 64%

Suppression of ING1 expression in sporadic breast cancer

et al. 1999

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“…A series of papers has also suggested that methylation of the BRCA1 promoter may be a signi®cant factor in decreasing BRCA1 expression in sporadic breast tumors, possibly through inactivation of a CREB site (Mancini et al, 1998). However, methylation can account for decreased BRCA1 expression only in a subset of sporadic breast cancer samples (Magdinier et al, 1998;Dobrovic and Simpfendorfer, 1997;Rice et al, 1998;Mancini et al, 1998;Catteau et al, 1999). Overall, these results suggest that sporadic breast cancer may result from defects in the genes regulating the BRCA1 promoter, or that transformation leads to a concomitant down regulation of BRCA1 expression.…”

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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“…BRCA1 mRNA levels are downregulated in sporadic breast cancers compared to normal breast tissues and hypermethylation of the promoter region of BRCA1 explains this downregulation in some cases. 13,14 However, BRCA2 mRNA levels do not show a consistent tendency and are both upregulated and downregulated among sporadic breast cancers. 15 Unlike BRCA1, the promoter region of BRCA2 is not hypermethylated.…”

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confidence: 99%

High BRCA2 mRNA expression predicts poor prognosis in breast cancer patients

Egawa

Miyoshi

Taguchi

et al. 2002

Intl Journal of Cancer

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The prognostic significance of BRCA 2 mRNA levels in tumor tissues was studied in sporadic breast cancer patients. BRCA 2 mRNA levels were determined by real-time PCR. Histologic grade III tumors showed significantly (p ‫؍‬ 0.001) higher BRCA 2 mRNA levels (0.828 ؎ 0.102 BRCA 2/␤-glucuronidase mRNA ratio, mean ؎ SE) than histologic grade I and II tumors (0.438 ؎ 0.055) and estrogen receptor (ER)-negative tumors (0.773 ؎ 0.102) showed a nonsignificant (p ‫؍‬ 0.072) trend toward an increase in BRCA 2 mRNA levels compared to ER-positive tumors (0.541 ؎ 0.079). Other clinicopathologic parameters, such as menopausal status, lymph node status and tumor size, were not significantly associated with BRCA 2 mRNA levels. Patients with high BRCA 2 mRNA levels showed a significantly (p ‫؍‬ 0.006) lower 5-year disease free survival rate (63%) than those with low levels (94%). Lymph node metastases, ER negativity and high histologic grade were also significantly (p < 0.05) associated with poor prognosis. Multivariate analysis revealed that BRCA 2 mRNA levels were a significant prognostic factor, being independent of the other conventional prognostic factors. Our results suggest that BRCA 2 mRNA levels might serve as a clinically useful prognostic factor in breast cancer patients. © 2002 Wiley-Liss, Inc. Key words: breast cancer; BRCA2; prognosis; ER; histologic grade BRCA1 and BRCA2 are the well-established breast cancer susceptibility genes and germline mutations of these genes are found in 20 -30% of breast cancer families. 1-4 BRCA1 and BRCA2 are typical tumor-suppressor genes and loss of a wild-type allele has been reported in almost all breast tumors arising in BRCA1 or BRCA2 germline mutation carriers. 5,6 Although the function of these genes remains to be established, both have been implicated in the repair of double-stranded DNA breaks in cooperation with Rad51 as well as in regulation of the G 2 -M checkpoint. 7 In addition, the ubiquitin ligase activity of the BRCA1-BARD1 complex has been described. 8 Somatic mutations of BRCA1 and BRCA2 appear to be very rare, 9 -12 but loss of heterozygosity of BRCA1 and BRCA2 is frequently observed, suggesting involvement of these genes in the pathogenesis of sporadic breast cancers. BRCA1 mRNA levels are downregulated in sporadic breast cancers compared to normal breast tissues and hypermethylation of the promoter region of BRCA1 explains this downregulation in some cases. 13,14 However, BRCA2 mRNA levels do not show a consistent tendency and are both upregulated and downregulated among sporadic breast cancers. 15 Unlike BRCA1, the promoter region of BRCA2 is not hypermethylated. 16 Thus, the contributions of BRCA1 and BRCA2 to the pathogenesis of sporadic breast cancers might be different.Downregulation of BRCA1 mRNA and protein levels is associated with an aggressive phenotype of sporadic breast cancers 17,18 and poor prognosis. 19 In contrast, Bieche et al. 15 reported that high BRCA2 mRNA levels are associated with an aggressive phenotype of sporadic breast cancer. We have...

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Aberrant methylation of the BRCA1 CpG island promoter is associated with decreased BRCA1 mRNA in sporadic breast cancer cells

Cited by 220 publications

References 21 publications

Suppression of ING1 expression in sporadic breast cancer

Suppression of ING1 expression in sporadic breast cancer

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

High BRCA2 mRNA expression predicts poor prognosis in breast cancer patients

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