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MYC overexpression and poor prognosis in sporadic breast cancer with BRCA1 deficiency

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Tumor Biology

Abstract

Breast cancer is a complex disease; the molecular mechanisms involved in sporadic breast carcinogenesis remain to be elucidated. The present study aimed to explore the deficiency of breast cancer susceptibility gene 1 (BRCA1), including protein loss expression, promoter hypermethylation and gene copy deletion, its correlationship with other tumor markers expression (TP53, MYC, etc.), and clinical significance in sporadic breast cancer. BRCA1 protein expression was negative in 226 of 374 (60.4 %) cases of this study. Cases negative for BRCA1 protein were more often with pathological tumor–node–metastasis stage III, positive for lymph node metastasis and MYC overexpression than BRCA1-positive tumors. BRCA1 hypermethylation was detected in 16.4 % (31 of 189) breast cancers, which correlated with BRCA1 negative, ER negative, MYC overexpression, and triple-negative phenotype. In addition, the percentage of cells with BRCA1 gene copy deletion was significantly increased in BRCA1-methylated tumors. Kaplan–Meier survival analysis showed that patients with BRCA1-negative expression showed a worse overall survival (OS) than those with BRCA1-positive expression, and patients with BRCA1-methylated tumors had a significantly worse disease-free survival than did patients with unmethylated tumors. Furthermore, BRCA1 hypermethylation showed an inverse association with OS in LN-positive or p53-negative subgroup patients. Importantly, uni- and multivariate Cox regression analyses revealed that BRCA1 was an independent prognostic indicator of OS in sporadic breast cancer. Thus, we found MYC overexpression and poor prognosis in sporadic breast cancer with BRCA1 deficiency. The targeting of BRCA1 deficiency in combination with MYC–pathways inhibitors may provide a promising strategy for sporadic breast cancer care, the triple-negative subtype in particular.

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References

  1. Forouzanfar MH, Foreman KJ, Delossantos AM, Lozano R, Lopez AD, Murray CJ, et al. Breast and cervical cancer in 187 countries between 1980 and 2010: a systematic analysis. Lancet. 2011;378:1461–84.

    Article  PubMed  Google Scholar 

  2. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90.

    Article  PubMed  Google Scholar 

  3. Knudson Jr AG. Hereditary cancer, oncogenes, and antioncogenes. Cancer Res. 1985;45:1437–43.

    PubMed  CAS  Google Scholar 

  4. Miki Y, Swensen J, Shattuck-Eidens D, Futreal PA, Harshman K, Tavtigian S, et al. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science. 1994;266:66–71.

    Article  PubMed  CAS  Google Scholar 

  5. Thompson ME, Jensen RA, Obermiller PS, Page DL, Holt JT. Decreased expression of BRCA1 accelerates growth and is often present during sporadic breast cancer progression. Nat Genet. 1995;9:444–50.

    Article  PubMed  CAS  Google Scholar 

  6. Rakha EA, El-Sheikh SE, Kandil MA, El-Sayed ME, Green AR, Ellis IO. Expression of BRCA1 protein in breast cancer and its prognostic significance. Hum Pathol. 2008;39:857–65.

    Article  PubMed  CAS  Google Scholar 

  7. Dapic V, Monteiro AN. Functional implications of BRCA1 for early detection, prevention, and treatment of breast cancer. Crit Rev Eukaryot Gene Expr. 2006;16:233–52.

    Article  PubMed  CAS  Google Scholar 

  8. Esteller M, Silva JM, Dominguez G, Bonilla F, Matias-Guiu X, Lerma E, et al. Promoter hypermethylation and BRCA1 inactivation in sporadic breast and ovarian tumors. J Natl Cancer Inst. 2000;92:564–9.

    Article  PubMed  CAS  Google Scholar 

  9. Catteau A, Morris JR. BRCA1 methylation: a significant role in tumour development? Semin Cancer Biol. 2002;12:359–71.

    Article  PubMed  CAS  Google Scholar 

  10. Atchley DP, Albarracin CT, Lopez A, Valero V, Amos CI, Gonzalez-Angulo AM, et al. Clinical and pathologic characteristics of patients with BRCA-positive and BRCA-negative breast cancer. J Clin Oncol. 2008;26:4282–8.

    Article  PubMed  Google Scholar 

  11. Smith KL, Isaacs C. BRCA mutation testing in determining breast cancer therapy. Cancer J. 2011;17:492–9.

    Article  PubMed  CAS  Google Scholar 

  12. Alvarez S, Diaz-Uriarte R, Osorio A, Barroso A, Melchor L, Paz MF, et al. A predictor based on the somatic genomic changes of the BRCA1/BRCA2 breast cancer tumors identifies the non-BRCA1/BRCA2 tumors with BRCA1 promoter hypermethylation. Clin Cancer Res. 2005;11:1146–53.

    PubMed  CAS  Google Scholar 

  13. Perez-Valles A, Martorell-Cebollada M, Nogueira-Vazquez E, Garcia-Garcia JA, Fuster-Diana E. The usefulness of antibodies to the BRCA1 protein in detecting the mutated BRCA1 gene. An immunohistochemical study. J Clin Pathol. 2001;54:476–80.

    Article  PubMed  CAS  Google Scholar 

  14. Wilson CA, Ramos L, Villasenor MR, Anders KH, Press MF, Clarke K, et al. Localization of human BRCA1 and its loss in high-grade, non-inherited breast carcinomas. Nat Genet. 1999;21:236–40.

    Article  PubMed  CAS  Google Scholar 

  15. Leake R, Barnes D, Pinder S, Ellis I, Anderson L, Anderson T, et al. Immunohistochemical detection of steroid receptors in breast cancer: a working protocol. UK Receptor Group, UK NEQAS, The Scottish Breast Cancer Pathology Group, and The Receptor and Biomarker Study Group of the EORTC. J Clin Pathol. 2000;53:634–5.

    Article  PubMed  CAS  Google Scholar 

  16. Naidu R, Wahab NA, Yadav M, Kutty MK. Protein expression and molecular analysis of c-myc gene in primary breast carcinomas using immunohistochemistry and differential polymerase chain reaction. Int J Mol Med. 2002;9:189–96.

    PubMed  CAS  Google Scholar 

  17. Bast Jr RC, Ravdin P, Hayes DF, Bates S, Fritsche Jr H, Jessup JM, et al. 2000 update of recommendations for the use of tumor markers in breast and colorectal cancer: clinical practice guidelines of the American Society of Clinical Oncology. J Clin Oncol. 2001;19:1865–78.

    PubMed  Google Scholar 

  18. Russo J, Yang X, Hu YF, Bove BA, Huang Y, Silva ID, et al. Biological and molecular basis of human breast cancer. Front Biosci. 1998;3:D944–60.

    PubMed  CAS  Google Scholar 

  19. Herman JG, Graff JR, Myohanen S, Nelkin BD, Baylin SB. Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands. Proc Natl Acad Sci U S A. 1996;93:9821–6.

    Article  PubMed  CAS  Google Scholar 

  20. Grunau C, Clark SJ, Rosenthal A. Bisulfite genomic sequencing: systematic investigation of critical experimental parameters. Nucleic Acids Res. 2001;29:E65–5.

    Article  PubMed  CAS  Google Scholar 

  21. Wei M, Grushko TA, Dignam J, Hagos F, Nanda R, Sveen L, et al. BRCA1 promoter methylation in sporadic breast cancer is associated with reduced BRCA1 copy number and chromosome 17 aneusomy. Cancer Res. 2005;65:10692–9.

    Article  PubMed  CAS  Google Scholar 

  22. Grushko T, Ridderstrale K, Olopade O, editors. Fluorescence in situ hybridization of BRCA1 gene in breast carcinoma. Handbook of immunohistochemistry and in situ hybridization of human carcinomas. San Diego: Elsevier Academic Press; 2004

  23. Pinkel D, Landegent J, Collins C, Fuscoe J, Segraves R, Lucas J, et al. Fluorescence in situ hybridization with human chromosome-specific libraries: detection of trisomy 21 and translocations of chromosome 4. Proc Natl Acad Sci U S A. 1988;85:9138–42.

    Article  PubMed  CAS  Google Scholar 

  24. Adachi PL, Camparoto ML, Sakamoto-Hojo ET, Brassesco MS, Peres LC. Fluorescent in situ hybridization in liver cell touch preparations from autopsy. Pathol Res Pract. 2005;201:41–7.

    Article  PubMed  Google Scholar 

  25. Kato H, Arakawa A, Suzumori K, Kataoka N, Young SR. FISH analysis of BRCA1 copy number in paraffin-embedded ovarian cancer tissue samples. Exp Mol Pathol. 2004;76:138–42.

    Article  PubMed  CAS  Google Scholar 

  26. Staff S, Nupponen NN, Borg A, Isola JJ, Tanner MM. Multiple copies of mutant BRCA1 and BRCA2 alleles in breast tumors from germ-line mutation carriers. Gene Chromosome Cancer. 2000;28:432–42.

    Article  CAS  Google Scholar 

  27. Birgisdottir V, Stefansson OA, Bodvarsdottir SK, Hilmarsdottir H, Jonasson JG, Eyfjord JE. Epigenetic silencing and deletion of the BRCA1 gene in sporadic breast cancer. Breast Cancer Res. 2006;8:R38.

    Article  PubMed  Google Scholar 

  28. Yang Q, Sakurai T, Mori I, Yoshimura G, Nakamura M, Nakamura Y, et al. Prognostic significance of BRCA1 expression in Japanese sporadic breast carcinomas. Cancer. 2001;92:54–60.

    Article  PubMed  CAS  Google Scholar 

  29. Thangaraju M, Kaufmann SH, Couch FJ. BRCA1 facilitates stress-induced apoptosis in breast and ovarian cancer cell lines. J Biol Chem. 2000;275:33487–96.

    Article  PubMed  CAS  Google Scholar 

  30. Galizia E, Giorgetti G, Piccinini G, Santinelli A, Loretelli C, Bianchi F, et al. BRCA1 expression in triple negative sporadic breast cancers. Anal Quant Cytol Histol. 2010;32:24–9.

    PubMed  Google Scholar 

  31. Miyamoto K, Fukutomi T, Asada K, Wakazono K, Tsuda H, Asahara T, et al. Promoter hypermethylation and post-transcriptional mechanisms for reduced BRCA1 immunoreactivity in sporadic human breast cancers. Jpn J Clin Oncol. 2002;32:79–84.

    Article  PubMed  Google Scholar 

  32. Matros E, Wang ZC, Lodeiro G, Miron A, Iglehart JD, Richardson AL. BRCA1 promoter methylation in sporadic breast tumors: relationship to gene expression profiles. Breast Cancer Res Treat. 2005;91:179–86.

    Article  PubMed  CAS  Google Scholar 

  33. Karray-Chouayekh S, Trifa F, Khabir A, Boujelbane N, Sellami-Boudawara T, Daoud J, et al. Clinical significance of epigenetic inactivation of hMLH1 and BRCA1 in Tunisian patients with invasive breast carcinoma. J Biomed Biotechnol. 2009;2009:369129.

    PubMed  Google Scholar 

  34. Singh AK, Pandey A, Tewari M, Shukla HS, Pandey HP. 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. 2011;20:478–83.

    Article  PubMed  Google Scholar 

  35. Xu X, Gammon MD, Zhang Y, Bestor TH, Zeisel SH, Wetmur JG, et al. BRCA1 promoter methylation is associated with increased mortality among women with breast cancer. Breast Cancer Res Treat. 2009;115:397–404.

    Article  PubMed  CAS  Google Scholar 

  36. Chen Y, Zhou J, Xu Y, Li Z, Wen X, Yao L, et al. BRCA1 promoter methylation associated with poor survival in Chinese patients with sporadic breast cancer. Cancer Sci. 2009;100:1663–7.

    Article  PubMed  CAS  Google Scholar 

  37. Lips EH, Mulder L, Oonk A, van der Kolk LE, Hogervorst FB, Imholz AL, et al. Triple-negative breast cancer: BRCAness and concordance of clinical features with BRCA1-mutation carriers. Br J Cancer 2013;108:2172–7

    Google Scholar 

  38. Wang Q, Zhang H, Kajino K, Greene MI. BRCA1 binds c-Myc and inhibits its transcriptional and transforming activity in cells. Oncogene. 1998;17:1939–48.

    Article  PubMed  CAS  Google Scholar 

  39. Li H, Lee TH, Avraham H. A novel tricomplex of BRCA1, Nmi, and c-Myc inhibits c-Myc-induced human telomerase reverse transcriptase gene (hTERT) promoter activity in breast cancer. J Biol Chem. 2002;277:20965–73.

    Article  PubMed  CAS  Google Scholar 

  40. Kennedy RD, Gorski JJ, Quinn JE, Stewart GE, James CR, Moore S, et al. BRCA1 and c-Myc associate to transcriptionally repress psoriasin, a DNA damage-inducible gene. Cancer Res. 2005;65:10265–72.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We are grateful for the collaboration received from the participating hospital and their staff. We are also grateful to Dr. Desheng Huang from the Department of Mathematics, College of Basic Medical Sciences, China Medical University, for statistical analysis. This study was supported by a grant of Minjie Wei from the National Natural Science Foundation of China (no. 30973559). This study was also supported by the science and technology project to Minjie Wei by Shenyang city (no. F11-264-1-19) and a grant to Ren Jie from the Doctoral Scientific Research Foundation of Liaoning Province of China (no. 20101141).

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Correspondence to Minjie Wei.

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Ren, J., Jin, F., Yu, Z. et al. MYC overexpression and poor prognosis in sporadic breast cancer with BRCA1 deficiency. Tumor Biol. 34, 3945–3958 (2013). https://doi.org/10.1007/s13277-013-0983-9

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