Carcinogenesis

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Carcinogenesis, Vol. 21, No. 9, 1761-1765, September 2000
© 2000 Oxford University Press

Short Communications

Methylation of the BRCA1 promoter is associated with decreased BRCA1 mRNA levels in clinical breast cancer specimens

Judd C. Rice¹, Hilmi Ozcelik^2,3, Patrick Maxeiner⁶, Irene Andrulis^4,5 and Bernard W. Futscher^1,6,7

¹ Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ 85721,
² Centre for Cancer Genetics, Samuel Lunenfeld Research Institute, and Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Tucson, AZ 85724, USA,
³ Department of Laboratory Medicine and Pathobiology,
⁴ Department of Molecular and Medical Genetics, University of Toronto and
⁵ Cancer Care Ontario, Toronto, Canada and
⁶ Bone Marrow Transplant Program, Arizona Cancer Center, Tucson, AZ 85724, USA

	Abstract

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Functional inactivation of BRCA1 is an important mechanism involved in breast cancer pathogenesis. Mutation is often responsible for BRCA1 inactivation in familial breast cancer, but is not responsible for the decreased levels of BRCA1 seen in a subset of sporadic breast cancer patients. To determine if aberrant cytosine methylation of the BRCA1 promoter is associated with decreased BRCA1 gene expression in human breast cancer, high resolution bisulfite sequence analysis was used to analyze the cytosine methylation status of the BRCA1 promoter in 21 axillary node negative breast cancer patients with known levels of BRCA1 expression. Aberrant cytosine methylation of the BRCA1 promoter was detected in three of 21 patient specimens. These three specimens also expressed the lowest levels of BRCA1. Results from this analysis show that aberrant cytosine methylation of the BRCA1 promoter is directly correlated with decreased levels of BRCA1 expression in human breast cancer, and suggest that epigenetic silencing may be one mechanism of transcriptional inactivation of BRCA1 in sporadic mammary carcinogenesis.

Abbreviations: HMEC, human mammary epithelial cells; PBL, peripheral blood lymphocytes.

	Introduction

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Mutation of the BRCA1 tumor suppressor gene is an important contributing factor in hereditary breast cancer; however, BRCA1 mutations have not been detected in the sporadic form of breast cancer (1,2). Despite the absence of BRCA1 mutations in sporadic breast cancer, BRCA1 mRNA and protein levels are reduced in a subset of sporadic human breast cancers and breast cancer cell lines (3–9). The decrease in BRCA1 function is associated with the conversion to a malignant phenotype (5,6), which can be reversed by forced re-expression of BRCA1 (10). These data suggest that transcriptional and/or post-transcriptional repression of BRCA1 may participate in the genesis of sporadic breast cancer.

One mechanism of transcriptional repression of tumor suppressor genes in human cancer is aberrant cytosine methylation of their CpG island gene promoters (11). This mechanism has been well documented for a number of genes involved in cancer, and includes Rb, p16, p15, E-cadherin, estrogen receptor and MGMT (12–18). Recently, we have shown that aberrant cytosine methylation of the BRCA1 CpG island is associated with transcriptional repression in human breast cancer cell lines (4). Other investigators have shown that aberrant methylation of BRCA1 occurs in human breast cancer specimens; however, BRCA1 expression was not evaluated in these clinical studies (19–22). Together, these data suggest that aberrant cytosine methylation of the BRCA1 promoter may participate in the transcriptional repression of BRCA1 gene expression in a subset of sporadic human breast cancers. To further test this hypothesis, the cytosine methylation status of the BRCA1 promoter in 21 axillary node negative breast cancer specimens with known levels of BRCA1 mRNA (23) were analyzed by high resolution bisulfite sequencing. The breast cancer samples analyzed in the present study are those from which tumor material was still available from the previous study. The results from these two analyses were blinded from one another until the study was completed.

The region of the BRCA1 CpG island analyzed contains 30 CpG sites, and is located from –567 to +44 relative to the BRCA1 exon1A transcription start site (Figure 1A). Within this region is a bi-directional core promoter (–218 to +1), that regulates the transcription of BRCA1, as well as the NBR2 gene, which lies in a head-to-head orientation 218 bp from the BRCA1 gene (24). This short CpG-rich stretch of BRCA1 5' flanking region contains 11 CpG sites and has previously been shown to contain strong promoter activity (25), to be unmethylated in normal human mammary epithelial cells (HMEC) (4) and is a target region for aberrant cytosine methylation in human breast cancer cell lines and tissue specimens (4,19–22).

View larger version (51K): [in this window] [in a new window]   Fig. 1. (A) Schematic representation of the BRCA1 CpG island analyzed by high resolution bisulfite sequencing. The open rectangles show the position of the first exon for the BRCA1 and NBR2 genes. The bent arrows show transcription start site and direction. The vertical lines indicate the positions of the 30 CpG sites analyzed, and the heavy horizontal bar shows the region of the BRCA1 core promoter. Numbers refer to the nucleotide position relative to BRCA1 transcription start (GenBank accession no. U37574). (B) Cytosine methylation status of the BRCA1 CpG island of 21 human breast cancer specimens. The methylation status of individual CpG sites was determined by comparison of the bisulfite sequence obtained with the known BRCA1 sequence. The y-axis represents the percent methylation at the 30 CpG sites in the region amplified; the x-axis represents the nucleotide position relative to the BRCA1 transcription start site. Percent methylation of each site was determined by dividing the number of methylated CpG sites at a specific site by the total number of clones analyzed (n = 20 in all cases). The line beneath each graph denotes the BRCA1 core promoter region.

 
Genomic DNA (500 ng) isolated from each of the breast cancer specimens was modified with sodium bisulfite using conditions described previously (26). Briefly, DNA was denatured with 0.3 M NaOH, reacted with 3.6 M sodium bisulfite (pH 5) at 55°C for 14 h, desalted by using a Wizard Prep kit (Promega), desulfonated with 0.3 M NaOH, and finally ethanol precipitated in preparation for PCR. The BRCA1 CpG island was amplified from the bisulfite-modified DNA by two rounds of PCR using nested primers specific to the bisulfite-modified sequence of the BRCA1 CpG island. These primer sequences and PCR conditions have been published previously (4). The resultant PCR product was cloned into the TA vector pGEM-T-Easy according to the manufacturer's instructions (Promega). For each breast cancer specimen, 20 positive recombinants were isolated using a plasmid miniprep kit (Qiagen), and sequenced on an ABI automated DNA sequencer. Percent methylation of each site was determined by dividing the number of methylated CpGs at a specific site by the total number of clones analyzed (n = 20 in all cases).

From these results, the percent methylation of the 30 CpG sites analyzed in the BRCA1 CpG island were calculated, and are shown graphically in Figure 1B. Normal HMEC and normal peripheral blood lymphocytes (PBL) are unmethylated in the 218 bp stretch of the BRCA1 core promoter with only low-level cytosine methylation detected at a few sporadic sites. Eighteen of the 21 breast cancer specimens were also largely unmethylated and similar to normal cells. In contrast, three of the 21 breast cancer specimens (1, 4 and 5) displayed patterns of aberrant cytosine methylation in the BRCA1 core promoter region. Two of the breast cancer specimens, 4 and 5, had extensive methylation of all 11 CpG sites in this region. Specimen 5 showed complete methylation at all CpG sites in all 20 of the bisulfite-sequenced PCR products. Specimen 4 showed allelic patterns of cytosine methylation, with ~30% of the DNA molecules showing extensive methylation throughout the promoter with the remainder being largely unmethylated (Figure 2). This allelic pattern most likely reflects many contributing factors, such as the presence of contaminating normal cells in the sample as well as heterogeneity within the tumor. As a representative example for comparison of allelic patterns of cytosine methylation another specimen (specimen 11) is shown in Figure 2. Each row of circles represents the cytosine methylation pattern from an individual clone, and the clones shown in Figure 2 were used to calculate the percent methylation of each CpG site for patient specimens 4 and 11 (Figure 1B). In contrast to specimen 4, specimen 11 had low levels of cytosine methylation at a number of CpG sites throughout the entire BRCA1 CpG island; however, in specimen 11 the sites of cytosine methylation were heterogeneously distributed among the separate alleles, and no extensively methylated alleles were detected.

View larger version (133K): [in this window] [in a new window]   Fig. 2. Allelic patterns of cytosine methylation in the BRCA1 CpG island of two breast cancer specimens. Each row of circles represents the cytosine methylation pattern obtained for individual clones of the BRCA1 CpG island PCR products obtained from patient specimens 4 and 11. These clones were used to calculate the percent methylation of each CpG site in these specimens (Figure 1B). The position of each CpG site relative to transcription start is shown. Open circles indicate unmethylated CpG sites, filled circles indicate methylated CpG sites. The heavy horizontal bar beneath each graph denotes the BRCA1 core promoter region.

 
Breast cancer specimen 1 showed a unique cytosine methylation pattern with 100 and 95% methylation, respectively, of two contiguous CpG sites (–37 and –29) within the core promoter region, whereas all other CpG sites remained unmethylated. Although only two of the 30 total CpG sites analyzed in specimen 1 were methylated, we considered this sufficient to be scored as aberrantly methylated because (i) these sites are unmethylated in normal tissue and (ii) this degree of cytosine methylation would be considered aberrant by other assays that measure cytosine methylation at one or a few sites (e.g. Southern blot). A search of transcription factor databases with the region encompassing these two CpG sites revealed the presence of a myb consensus sequence. The myb family of DNA-binding proteins is involved in normal breast development and their binding to their DNA consensus sequence has been shown to be inhibited by cytosine methylation (27–29); however, the functional significance of the pattern of aberrant cytosine methylation observed in specimen 1, if any, remains unknown.

The 19 CpG sites analyzed outside the BRCA1 core promoter region (11 upstream and six downstream) are completely unmethylated in normal HMEC, whereas PBL showed high methylation of the two most distal 5' CpG sites analyzed (–565 and –567). These sites may represent a rough 5' boundary of the CpG island, as sites immediately upstream become increasingly methylated in both normal and tumor tissue (data not shown). Similar to the results obtained for the BRCA1 core promoter region, specimens 4 and 5 were extensively methylated at the remaining 19 CpG sites. In contrast, all other samples, including specimen 1, were largely unmethylated and similar to normal cells. Although non-CpG cytosine methylation has been reported to exist in the mammalian genome (30), non-CpG cytosine methylation was not detected in any of the normal or tumor tissues analyzed.

Following completion of the cytosine methylation analysis, the level of BRCA1 gene expression for each of the breast cancer specimens was unblinded. BRCA1 expression for each breast cancer specimen relative to normal HMEC (23) is shown in Table I, as is their BRCA1 cytosine methylation status. Four of the 21 breast cancer specimens (1, 4, 5 and 11) expressed levels of BRCA1 of one-half or less compared with normal HMEC. Of these specimens, the three with the lowest relative levels of BRCA1 gene expression also displayed aberrant cytosine methylation of the BRCA1 core promoter region (1, 4 and 5). In contrast, aberrant cytosine methylation of BRCA1 was not detected in any of the 17 specimens that expressed BRCA1 at levels similar to normal cells (i.e. >0.5).

View this table: [in this window] [in a new window]   Table I. BRCA1 mRNA levels and cytosine methylation status in 21 breast cancer specimens

 
In this study, three of 21 (14%) breast cancer specimens showed aberrant cytosine methylation of the BRCA1 CpG island. This frequency of aberrant cytosine methylation of the BRCA1 core promoter in the breast cancer specimens analyzed in this study is consistent with other studies that have analyzed BRCA1 (3,19–22). Using bisulfite sequencing Mancini et al. (22) detected aberrant methylation in two of six breast cancer specimens. Using Southern blot analysis to analyze cytosine methylation of BRCA1, Catteau et al. detected aberrant BRCA1 methylation in 10 of 96 breast cancer specimens and Dobrovic and co-workers detected aberrant BRCA1 methylation in four of 18 patients over the course of two studies, whereas Magdinier et al. did not detect aberrant methylation in any of the 37 patients analyzed in their study (3,19–21). A simple compilation of the data from our study and the four studies listed above shows that 19 of 178 (11%) breast cancer specimens displayed aberrant methylation of BRCA1. Together, these data probably provide a reasonable estimate of the frequency of aberrant methylation of BRCA1 in sporadic breast cancer. Furthermore, this estimated frequency of aberrant methylation of the BRCA1 CpG island in sporadic breast cancer is lower than the frequency of decreased BRCA1 expression in sporadic breast cancer (7–9), indicating that it is likely that multiple mechanisms exist for the inactivation of BRCA1 function in sporadic breast cancer.

The present study extends the earlier studies on BRCA1 by providing a direct correlation between methylation of the BRCA1 core promoter and transcriptional repression of the BRCA1 gene in sporadic human breast cancer, and suggests that 5-methylcytosine-associated inactivation of BRCA1 may be important in sporadic breast cancer. As forced re-expression of BRCA1 inhibits the malignant phenotype, reversal of BRCA1 promoter methylation may be a potential therapeutic strategy for a subset of sporadic breast cancer patients.

	Notes

 
⁷ To whom correspondence should be addressed Email: bfutscher{at}azcc.arizona.edu

	Acknowledgments

 
We thank Nick Holtan for laboratory assistance and Skip Vaught and his sequencing crew at the Laboratory of Systematics and Evolution, University of Arizona for the automated DNA sequencing. This work is dedicated to the memory of Patrick Maxeiner (1975–2000). This work was supported by Department of Army grant DAMD17-98-1-8279 to B.W.F.

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Received March 21, 2000; revised May 18, 2000; accepted May 24, 2000.

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