Abstract
BRCA1 mutations have been associated with hereditary breast cancer only. Recent studies indicate that a subgroup of sporadic breast cancer might also be associated with reduction in BRCA1 mRNA levels and protein expression. However, the mechanism of reduced mRNA and protein expression is yet not fully elucidated. This study aims to assess BRCA1 protein expression and the role of BRCA1 promoter methylation in sporadic breast cancer in North Indian population and to correlate these with known prognostic factors and molecular profiles of breast cancer. BRCA1 protein expression was normal (>50 % tumour cells) in 41 (43 %) cases, reduced (20–50 % tumour cells) in 33 (35 %) cases and absent/markedly reduced (<20 % tumour cells) in 21 (22.1 %) cases. Cases which were negative for BRCA1 protein were more frequently positive for basal markers (29 versus 5 %) and were more often ER-negative (62 versus 39 %) than BRCA1-positive tumours. Methylation of BRCA1 promoter region was seen in 11/45 cases (24 %). All 11 cases showing BRCA1 methylation had absent (eight cases) or reduced (three cases) BRCA1 protein expression. BRCA1 protein-negative tumours were more frequently basal marker-positive and ER-negative, highlighting the ‘BRCAness’ of sporadic breast cancer with loss of BRCA1 protein expression through promoter hypermethylation similar to hereditary breast cancer with BRCA1 mutations. Loss of BRCA1 in sporadic breast cancer suggests that therapeutics targeting BRCA1 pathway in hereditary breast cancer like PARP inhibitors might be used as therapeutic targets for sporadic breast tumours.
Similar content being viewed by others
References
Easton DF, Bishop DT, Ford D (1993) Genetic linkage analysis in familial breast and ovarian cancer: results from 214 families. The Breast Cancer Linkage Consortium. Am J Hum Genet 52:678–701
Claus EB, Schildkraut JM, Thompson WD (1996) The genetic attributable risk of breast and ovarian cancer. Cancer 77:2318–2324
Futreal PA, Liu Q, Shattuck-Eidens D, Cochran C, Harshman K, Tavtigian S (1994) BRCA1 mutations in primary breast and ovarian carcinomas. Science 266:120–122
Lancaster JM, Wooster R, Mangion J et al (1996) BRCA2 mutations in primary breast and ovarian cancers. Nat Genet 13:238–240
Johnson SM, Shaw JA, Walker RA (2002) Sporadic breast cancer in young women: prevalence of loss of heterozygosity at p53, BRCA1 and BRCA2. Int J Cancer 98:205–209
Herman JG, Baylin SB (2003) Gene silencing in cancer in association with promoter hypermethylation. N Engl J Med 349:2042–2054
Kim MJ, Ro JY, Ahn SH et al (2006) Clinicopathologic significance of the basal-like subtype of breast cancer: a comparison with hormone receptor and Her2/neuoverexpressing phenotypes. Hum Pathol 37:1217–1226
DeVargas RL, Michor F (2011) Evolutionary dynamics of BRCA1 alterations in breast tumorigenesis. J Theor Biol 273:207–215
Valentin MD, da Silva SD, Privat M, Alaoui-Jamali M, Bignon YB (2012) Molecular insights on basal-like breast cancer. Breast Canc Res Treat 2012 Jan 11 [Epub ahead of print]
Santarosa M, Maestro R (2012) BRACking news on triple-negative/basal-like breast cancers: how BRCA1 deficiency may result in the development of a selective tumor subtype. Cancer Metastasis Rev 31:131–142
Warmoes M, Jaspers JE, Pham TV et al (2012) Proteomics of mouse BRCA1-deficient mammary tumors identifies DNA repair proteins with diagnostic and prognostic value in human breast cancer. Mol Cell Proteomics 2012 Feb 24 [Epub ahead of print]
Da Pang, Zhao Y, Xue W et al (2011) Methylation profiles of the BRCA1 promoter in hereditary and sporadic breast cancer among Han Chinese. Med Oncol 2011 Nov 11 [Epub ahead of print]
Ibragimova I, Cairns P (2011) Assays for hypermethylation of the BRCA1 gene promoter in tumor cells to predict sensitivity to PARP-inhibitor therapy. Meth Mol Biol 780:277–291
Jaspers JE, Rottenberg S, Jonkers J (2009) Therapeutic options for triple negative breast cancers with defective homologous recombination. Biochim Biophys Acta 1796:266–280
Tutt A, Robson M, Garber JE et al (2010) Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof of-concept trial. Lancet 376:235–244
Taylor J, Lymboura M, Pace PE et al (1998) An important role for BRCA1 in breast cancer progression is indicated by its loss in a large proportion of non-familial breast cancers. Int J Cancer 79:334–342
Rakha EA, El-Sheikh SE, Kandil MA et al (2008) Expression of BRCA1 protein in breast cancer and its prognostic significance. Hum Pathol 39:857–865
Lambie H, Miremadi A, Pinder SE et al (2003) Prognostic significance of BRCA1 expression in sporadic breast carcinomas. J Pathol 200:207–213
Nielsen TO, Hsu FD, Jensen K (2004) Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma. Clin Cancer Res 10:5367–5374
Abd El-Rehim DM, Pinder SE, Paish CE (2004) Expression of luminal and basal cytokeratins in human breast carcinoma. J Pathol 203:661–671
Foulkes WD, Ingunn MS, Chappuis PO et al (2003) Germline BRCA1 mutations and a basal epithelial phenotype in breast cancer. J Natl Cancer Inst 95:19
Singha AK, Pandey A, Tewarib M, Shukla HS, Pandey HP (2011) Epigenetic silencing of BRCA1 gene associated with demographic and pathologic factors in sporadic breast cancer: a study of an Indian population. Eur J Cancer Prev 20:478–483
Ben GR, Hachana M, Ziadi S et al (2011) Contribution of epigenetic alteration of BRCA1 and BRCA2 genes in breast carcinomas in Tunisian patients. Canc Epidemiol Oct 4, (Epub ahead of print)
Jones PA, Baylin SB (2002) The fundamental role of epigenetic events in cancer. Nat Rev Genet 3:415–428
Birgisdottir V, Stefansson OA (2006) Epigenetic silencing and deletion of the BRCA1 gene in sporadic breast cancer. Breast Cancer Res 8:R38
Foulkes WD, Stefansson IM, Chappuis PO et al (2003) Germline BRCA1 mutations and a basal epithelial phenotype in breast cancer. J Natl Cancer Inst 95:1482–1485
Esteller M (2002) CpG island hypermethylation and tumor suppressor genes: a booming present, a brighter future. Oncogene 21:5427–5440
Baylin SB, Ohm JE (2006) Epigenetic gene silencing in cancer: a mechanism for early oncogenic pathway addiction? Nat Rev Cancer 6:107–116
Esteller M, Silva JM, Dominguez G, Bonilla F, Matias-Guiu X, Lerma E (2000) Promoter hypermethylation and BRCA1 inactivation in sporadic breast and ovarian tumors. J Natl Cancer Inst 92:564–569
Xu CF, Brown MA, Chambers JA et al (1995) Distinct transcription start sites generate two forms of BRCA1 mRNA. Hum Mol Genet 4:2259–2264
Catteau A, Morris JR (2002) BRCA1 methylation: a significant role in tumour development? Semin Cancer Biol 12:359–371
Mirza S, Sharma G, Prasad CP et al (2007) Promoter hypermethylation of TMS1, BRCA1, ERα and PRB in serum and tumor DNA of invasive ductal breast carcinoma patients. Life Sci 81:280–287
Raju Bagadi SA, Prasad CP, Kaur J et al (2008) Clinical significance of promoter hypermethylation of RASSF1A, RARβ2, BRCA1 and HOXA5 in breast cancers of Indian patients. Life Sci 82:1288–1292
Conflict of interest
The authors declare that they have no financial or non-financial conflict of interests.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Bal, A., Verma, S., Joshi, K. et al. BRCA1-methylated sporadic breast cancers are BRCA-like in showing a basal phenotype and absence of ER expression. Virchows Arch 461, 305–312 (2012). https://doi.org/10.1007/s00428-012-1286-z
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00428-012-1286-z