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Promoter Hypermethylation and BRCA1 Inactivation in Sporadic Breast and Ovarian Tumors
Abstract
BACKGROUND: Inherited mutations in the BRCA1 gene may be responsible for almost half of inherited breast carcinomas. However, somatic (acquired) mutations in BRCA1 have not been reported, despite frequent loss of heterozygosity (LOH or loss of one copy of the gene) at the BRCA1 locus and loss of BRCA1 protein in tumors. To address whether BRCA1 may be inactivated by pathways other than mutations in sporadic tumors, we analyzed the role of hypermethylation of the gene's promoter region. METHODS: Methylation patterns in the BRCA1 promoter were assessed in breast cancer cell lines, xenografts, and 215 primary breast and ovarian carcinomas by methylation-specific polymerase chain reaction (PCR). BRCA1 RNA expression was determined in cell lines and seven xenografts by reverse transcription-PCR. P values are two-sided. RESULTS: The BRCA1 promoter was found to be unmethylated in all normal tissues and cancer cell lines tested. However, BRCA1 promoter hypermethylation was present in two breast cancer xenografts, both of which had loss of the BRCA1 transcript. BRCA1 promoter hypermethylation was present in 11 (13%) of 84 unselected primary breast carcinomas. BRCA1 methylation was strikingly associated with the medullary (67% methylated; P =.0002 versus ductal) and mucinous (55% methylated; P =.0033 versus ductal) subtypes, which are overrepresented in BRCA1 families. In a second series of 66 ductal breast tumors informative for LOH, nine (20%) of 45 tumors with LOH had BRCA1 hypermethylation, while one (5%) of 21 without LOH was methylated (P =.15). In ovarian neoplasms, BRCA1 methylation was found only in tumors with LOH, four (31%) of 13 versus none of 18 without LOH (P =.02). The BRCA1 promoter was unmethylated in other tumor types. CONCLUSION: Silencing of the BRCA1 gene by promoter hypermethylation occurs in primary breast and ovarian carcinomas, especially in the presence of LOH and in specific histopathologic subgroups. These findings support a role for this tumor suppressor gene in sporadic breast and ovarian tumorigenesis.
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“Given that changes in BRCA1 promoter status contribute to sporadic tumors [64,65], mutations outside the reading frame or changes in promoter methylation status could alter FANCJ expression and contribute to tumorigenesis.”
From Hereditary Breast Cancer and the BRCA1-Associated FANCJ/BACH1/BRIP1 (2011) · cites this paper as [65]
In the citing paper
“Given that changes in BRCA1 promoter status contribute to sporadic tumors [64,65], mutations outside the reading frame or changes in promoter methylation status could alter FANCJ expression and contribute to tumorigenesis.”
From Hereditary Breast Cancer and the BRCA1-Associated FANCJ/BACH1/BRIP1 (2011) · cites this paper as [65]
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“For example, the silencing of the BRCA1 gene through promoter hypermethylation has been demonstrated in breast and ovarian cancers (149), which highlights the importance of also considering functional biomarker assays, rather than relying on genomics in isolation.”
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“It has been proposed that somatic loss of BRCA function by promoter methylation and consequent transcriptional silencing may also induce HR deficiency, which would result in an additional fraction of patients who may potentially benefit from PARP inhibitors (33).”
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“Furthermore, decreased Brca1 expression due to hypermethylation of the Brca1 promoter is a common event in multiple nonhereditary cancer types (21, 22), and a loss of functional Brca1 was reported to cause radiosensitization in tumors (23, 24), suggesting that the methylation status of the Brca1 promoter can potential…”
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BackgroundThe p53 pathway in breast cancer
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“Aberrant methylation of the BRCA1 promoter is found in 11%–14% of sporadic BCs.(35,38) In contrast, BRCA2 tumors lack a clear pathological phenotype.”
BackgroundInfluential“Platinum resistant” ovarian cancer: What is it, who to treat and how to measure benefit?
Davis, A., Tinker, A. V., & Friedlander, M. (2014) · Gynecologic Oncology · doi:10.1016/j.ygyno.2014.02.038 · Cited by 433
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“Supplementary Figure S5: Quantitative determination of DNA demethylation level at the target CpG sites in BRCA1 promoter .”
BackgroundLok, B. H., Gardner, E. E., Schneeberger, V. E., Ni, A., Desmeules, P., Rekhtman, N., de Stanchina, E., Teicher, B. A., Riaz, N., Powell, S. N., et al. (2016) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-16-1040 · Cited by 350
“Beyond inactivating mutations in known mediators of HR such as BRCA1/2, other mechanisms may result in HR deficiency in sporadic tumors, including epigenetic silencing of BRCA1 and HR pathway disruptions in other known and unknown mediators of this pathway(15, 16).”
BackgroundRelevance of DNA methylation in the management of cancer
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Self-citationBRCA1 promoter region hypermethylation in ovarian carcinoma: a population-based study.
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de Ruijter, T. C., Veeck, J., de Hoon, J. P. J., van Engeland, M., & Tjan‐Heijnen, V. C. G. (2010) · Journal of Cancer Research and Clinical Oncology · doi:10.1007/s00432-010-0957-x · Cited by 329
“For instance, gene inactivation by promoter methylation of BRCA1 is a common lesion among sporadic breast tumours (Esteller et al. 2000).”
Targeting epigenetic regulators to overcome drug resistance in cancers
Wang, N., Ma, T., & Yu, B. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01341-7 · Cited by 334
“In breast and ovarian cancers, the DNA repair gene BRCA1 is also silenced because of hypermethylation.(41) There are five members in the DNA methyltransferase family, namely DNMT1, DNMT2, DNMT3A, DNMT3B, and DNMT3L.”
BackgroundThe DNA methylation landscape in cancer
Skvortsova, K., Stirzaker, C., & Taberlay, P. C. (2019) · Essays in Biochemistry · doi:10.1042/ebc20190037 · Cited by 325
Cancer Stem Cells Contribute to Cisplatin Resistance in Brca1/p53 –Mediated Mouse Mammary Tumors
Shafee, N., Smith, C. R., Wei, S., Kim, Y. H., Mills, G. B., Hortobágyi, G. N., Stanbridge, E. J., & Lee, E. Y.-H. P. (2008) · Cancer Research · doi:10.1158/0008-5472.can-07-5480 · Cited by 308
“In sporadic breast cancer, BRCA1 mutations are rare; however, significant percentages of sporadic cancers show reduced or absent expression of BRCA1 due to promoter hypermethylation (3).”
BackgroundBRCA1 mRNA expression levels as an indicator of chemoresistance in lung cancer
Tarón, M., Rosell, R., Felip, E., Méndez, P., Souglakos, J., Ronco, M. S., Queralt, C., Majo, J., Sánchez, J. M., Sánchez, J. J., et al. (2004) · Human Molecular Genetics · doi:10.1093/hmg/ddh260 · Cited by 308
“Aberrant cytosine methylation of the BRCA1 CpG island promoter may be a partial mechanism of BRCA1 repression in sporadic breast cancer (26,27).”
BackgroundBRCA1 Mutation Analysis of 41 Human Breast Cancer Cell Lines Reveals Three New Deleterious Mutants
Elstrodt, F., Hollestelle, A., Nagel, J. H. A., Gorin, M. A., Wasielewski, M., van den Ouweland, A., Merajver, S. D., Ethier, S. P., & Schutte, M. E. M. (2006) · Cancer Research · doi:10.1158/0008-5472.can-05-2853 · Cited by 306
Distinct gene mutation profiles among luminal-type and basal-type breast cancer cell lines
Hollestelle, A., Nagel, J. H. A., Smid, M., Lam, S., Elstrodt, F., Wasielewski, M., Ng, S. S., French, P. J., Peeters, J. K., Rozendaal, M. J., et al. (2009) · Breast Cancer Research and Treatment · doi:10.1007/s10549-009-0460-8 · Cited by 308
“Promoter hypermethylation was determined for BRCA1, E-cadherin, p16, p14ARF and RB1, by azacytidine assays and/or methylation-specific PCR ([23]; Hollestelle et al.”
MethodThe epigenetics of breast cancer
Jovanovic, J., Rønneberg, J. A., Tost, J., & Kristensen, V. N. (2010) · Molecular Oncology · doi:10.1016/j.molonc.2010.04.002 · Cited by 310
Kondrashova, O., Topp, M. D., Nesic, K., Lieschke, E., Ho, G., Harrell, M. I., Zapparoli, G. V., Hadley, A., Hollian, R., Boehm, E., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-05564-z · Cited by 304
BRCA locus-specific loss of heterozygosity in germline BRCA1 and BRCA2 carriers
Maxwell, K. N., Wubbenhorst, B., Wenz, B. M., De Sloover, D., Pluta, J., Emery, L., Barrett, A., Kraya, A. A., Anastopoulos, I. N., Yu, S., et al. (2017) · Nature Communications · doi:10.1038/s41467-017-00388-9 · Cited by 296
Ovarian carcinomas with genetic and epigenetic BRCA1 loss have distinct molecular abnormalities
Press, J. Z., Luca, A. D., Boyd, N., Young, S. S., Troussard, A. A., Ridge, Y., Kaurah, P., Kalloger, S. E., Blood, K. A., Smith, M. J., et al. (2008) · BMC Cancer · doi:10.1186/1471-2407-8-17 · Cited by 287
DNA Repair Pathways in Clinical Practice: Lessons From Pediatric Cancer Susceptibility Syndromes
Kennedy, R. D., & D’Andrea, A. D. (2006) · Journal of Clinical Oncology · doi:10.1200/jco.2005.05.4171 · Cited by 290
Bosch, A., Eroles, P., Zaragozá, R., Vinã, J. R., & Lluch, A. M. (2010) · Cancer Treatment Reviews · doi:10.1016/j.ctrv.2009.12.002 · Cited by 288
DNA Methylation Profiling: An Emerging Paradigm for Cancer Diagnosis
Papanicolau‐Sengos, A., & Aldape, K. (2021) · Annual Review of Pathology Mechanisms of Disease · doi:10.1146/annurev-pathol-042220-022304 · Cited by 285
Gene Expression Profiles of BRCA1-Linked, BRCA2-Linked, and Sporadic Ovarian Cancers
Jazaeri, A. A., Yee, C. J., Sotiriou, C. P., Brantley, K., Boyd, J. A., & Liu, E. T. (2002) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/94.13.990 · Cited by 282
“Although the clinical significance of this observation remains unclear (31), the fact that BRCA1 promoter hypermethylation is observed selectively in breast and ovarian tumors and not in other tumors provides circumstantial evidence for its pathologic significance ( 27 ,29).”
Backgroundde Cáceres, I. I., Battagli, C., Esteller, M., Herman, J. G., Dulaimi, E., Edelson, M. I., Bergman, C. A., Ehya, H., Eisenberg, B. L., & Cairns, P. (2004) · Cancer Research · doi:10.1158/0008-5472.can-04-1529 · Cited by 280
“Using sensitive methylation-specific PCR, we screened matched tumor, preoperative serum or plasma, and peritoneal fluid (washes or ascites) DNA obtained from 50 patients with ovarian or primary peritoneal tumors for hypermethylation status of the normally unmethylated BRCA1 and RAS association domain family protein 1A…”
BackgroundInfluentialSelf-citationDammann, R., Yang, G., & Pfeifer, G. P. (2001) · PubMed · Cited by 280
Prat, J., D′Angelo, E., & Espinosa, Í. (2018) · Human Pathology · doi:10.1016/j.humpath.2018.06.018 · Cited by 283
DNA Damage Response Genes and the Development of Cancer Metastasis
Broustas, C. G., & Lieberman, H. B. (2014) · Radiation Research · doi:10.1667/rr13515.1 · Cited by 284
“Loss of BRCA1 expression by promoter hypermethylation is also seen in nonhereditary breast and ovarian cancer (73).”
BackgroundRosen, E. M., Fan, S., Pestell, R. G., & Goldberg, I. D. (2003) · Journal of Cellular Physiology · doi:10.1002/jcp.10257 · Cited by 279
“…about 10–15% of sporadic breast and ovarian cancer cases exhibit hyper-methylation of the BRCA1 promoter, associated with a reduction of BRCA1 mRNA expression (Baldwin et al., 2000; Esteller et al., 2000; Magdinier et al., 2000; Rice and Futscher, 2000; Rice et al., 2000; Chan et al., 2002).”
BackgroundTriple negative breast cancers: Clinical and prognostic implications
Dawson, S., Provenzano, E., & Caldas, C. (2009) · European Journal of Cancer · doi:10.1016/s0959-8049(09)70013-9 · Cited by 269
The Role of DNA Methylation in Cancer
Lakshminarasimhan, R., & Liang, G. (2016) · Advances in experimental medicine and biology · doi:10.1007/978-3-319-43624-1_7 · Cited by 281
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“In a fraction of these tumours, this low BRCA1 expression could be due to 2011 EMBO Molecular Medicine 279 280 aberrant methylation of the promoter, which was reported in 11–14% of breast cancer cases (Catteau et al, 1999; Esteller et al, 2000; Rice et al, 2000; Turner et al, 2007).”
BackgroundEpigenetic inactivation of the premature aging Werner syndrome gene in human cancer
Agrelo, R., Cheng, W.-H., Setien, F., Ropero, S., Espada, J., Fraga, M. F., Herranz, M., Paz, M. F., Sanchez-Cespedes, M., Artiga, M. J., et al. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0600645103 · Cited by 264
Self-citationShames, D. S., Girard, L., Gao, B., Sato, M., Lewis, C. M., Shivapurkar, N., Jiang, A., Perou, C. M., Kim, Y. H., Pollack, J. R., et al. (2006) · PLoS Medicine · doi:10.1371/journal.pmed.0030486 · Cited by 263
“Several other genes exhibit a similar, restricted methylation profile, such as breast cancer 1, early onset (BRCA1) in breast and ovarian tumors, and glutathione S-transferase pI (GSTP1) in liver and prostate cancers [59,60].”
BackgroundDrew, Y., Mulligan, E. A., Vong, W., Thomas, H. D., Kahn, S., Kyle, S., Mukhopadhyay, A., Los, G., Hostomský, Z., Plummer, E. R., et al. (2010) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/djq509 · Cited by 265
“Moreover, epigenetic gene inactivation by promoter CpG island methylation is a well-recognized mechanism for silencing tumor suppressor genes (10), and BRCA1 methylation has been reported in approximately 15% of sporadic breast and ovarian cancers (11,12).”
BackgroundThe role of DNA methylation in cancer development.
Łuczak, M. W., & Jagodziński, P. P. (2006) · PubMed · doi:10.5603/4561 · Cited by 257
Epigenetic lesions causing genetic lesions in human cancer
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“Furthermore, particular breast histological subtypes overrepresented in the familial tumours are also especially rich in aberrant methylation [32].”
BackgroundSelf-citationOsborne, C., Wilson, P., & Tripathy, D. (2004) · The Oncologist · doi:10.1634/theoncologist.9-4-361 · Cited by 283
“However, methylation of the gene has been found in sporadic cases and in familial cases with a normal BRCA-1 sequence [ 101 ].”
BackgroundTargeting Epigenetics in Cancer
Bennett, R. L., & Licht, J. D. (2017) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-010716-105106 · Cited by 254
The Science behind Microgreens as an Exciting New Food for the 21st Century
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Metadata
- Authors
- Esteller, M.
- Affiliations
- Roswell Park Comprehensive Cancer Center (US)
- Corresponding author
- Esteller, M.
- ORCID
- Esteller, M.
- Venue
- Journal of the National Cancer Institute
- Publisher
- Oxford University Press (OUP)
- Published
- 2000-04-05
- Volume
- 92
- Issue
- 7
- Pages
- 564-569
- ISSN
- 0027-8874 (ISSN-L)
- 1460-2105
- OpenAlex
- W2160234594
- Cited by
- 1,233
- References
- 41
- Citations by year
- 2026: 20 · 2025: 33 · 2024: 37 · 2023: 46 · 2022: 49 · 2021: 40 · 2020: 53 · 2019: 43 · 2018: 60 · 2017: 48 · 2016: 52 · 2015: 69 · 2014: 56 · 2013: 57 · 2012: 69
- FWCI
- 22.63
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- JNCI Journal of the National Cancer Institute (publishedVersion)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- Funders
- National Cancer Institute (R01CA043318, CA 43318)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › BRCA gene mutations in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Health Sciences › Medicine › Pathology and Forensic Medicine › Breast Lesions and Carcinomas
- Keywords
- BRCA1 promoter hypermethylation, sporadic breast cancer, ovarian cancer, loss of heterozygosity, gene silencing, tumor suppressor, medullary breast carcinoma, mucinous breast carcinoma, histological subtypes, epigenetic silencing, breast cancer xenografts
- MeSH terms
- Breast Neoplasms, Female, Humans, Methylation, Ovarian Neoplasms, Promoter Regions, Genetic, RNA, RNA, Neoplasm, Transplantation, Heterologous, Tumor Cells, Cultured, Gene Expression Regulation, Neoplastic, Carcinoma, Ductal, Breast, Genes, BRCA1, Loss of Heterozygosity, Reverse Transcriptase Polymerase Chain Reaction
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