Skip to main content
Top
Published in: Breast Cancer Research and Treatment 1/2012

01-08-2012 | Preclinical study

BRCA1 promoter methylation status does not predict response to tamoxifen in sporadic breast cancer patients

Authors: Jasmina Z. Cerne, Lin Zong, Jaroslav Jelinek, Susan G. Hilsenbeck, Tao Wang, Steffi Oesterreich, Sean E. McGuire

Published in: Breast Cancer Research and Treatment | Issue 1/2012

Login to get access

Abstract

The purpose of this study is to investigate whether BRCA1 promoter methylation is associated with poorer outcome in sporadic breast cancer cases treated with tamoxifen. BRCA1 promoter methylation was determined by bisulfite pyrosequencing in two groups of sporadic breast cancer patients, systemically untreated (N = 497) and treated with adjuvant tamoxifen (N = 497). Associations of BRCA1 promoter methylation with clinopathological characteristics and the effect of BRCA1 promoter methylation on time to first recurrence (TTR) and overall survival (OS) were examined. No significant differences were observed between BRCA1 promoter methylation and clinopathological characteristics in untreated and tamoxifen-treated groups. Cut point analysis did not find any promising cut point for BRCA1 promoter methylation that would differentially influence TTR and OS in untreated and tamoxifen-treated group. Using the median (2.53 %) and an arbitrary value of 10 % as a cut point for methylation, we still found no significant effect of BRCA1 promoter methylation on TTR and OS in untreated and tamoxifen-treated group. Despite data suggesting that BRCA1 levels impact estrogen receptor response to tamoxifen, our results indicate that BRCA1 promoter methylation is not associated with poorer outcome in sporadic breast cancer cases treated with tamoxifen.
Literature
2.
go back to reference Thompson ME, Jensen RA, Obermiller PS, Page DL, Holt JT (1995) Decreased expression of BRCA1 accelerates growth and is often present during sporadic breast cancer progression. Nat Genet 9:444–450PubMedCrossRef Thompson ME, Jensen RA, Obermiller PS, Page DL, Holt JT (1995) Decreased expression of BRCA1 accelerates growth and is often present during sporadic breast cancer progression. Nat Genet 9:444–450PubMedCrossRef
3.
go back to reference Mueller CR, Roskelley CD (2003) Regulation of BRCA1 expression and its relationship to sporadic breast cancer. Breast Cancer Res 5:45–52PubMedCrossRef Mueller CR, Roskelley CD (2003) Regulation of BRCA1 expression and its relationship to sporadic breast cancer. Breast Cancer Res 5:45–52PubMedCrossRef
4.
go back to reference Dobrovic A, Simpfendorfer D (1997) Methylation of the BRCA1 gene in sporadic breast cancer. Cancer Res 57:3347–3350PubMed Dobrovic A, Simpfendorfer D (1997) Methylation of the BRCA1 gene in sporadic breast cancer. Cancer Res 57:3347–3350PubMed
5.
go back to reference Mancini DN, Rodenhiser DI, Ainsworth PJ, O’Malley FP, Singh SM, Xing W et al (1998) CpG methylation within the 5’ regulatory region of the BRCA1 gene is tumor specific and includes a putative CREB binding site. Oncogene 16:1161–1169PubMedCrossRef Mancini DN, Rodenhiser DI, Ainsworth PJ, O’Malley FP, Singh SM, Xing W et al (1998) CpG methylation within the 5’ regulatory region of the BRCA1 gene is tumor specific and includes a putative CREB binding site. Oncogene 16:1161–1169PubMedCrossRef
6.
go back to reference Rice JC, Massey-Brown KS, Futscher BW (1998) Aberrant methylation of the BRCA1 CpG island promoter is associated with decreased BRCA1 mRNA in sporadic breast cancer cells. Oncogene 17:1807–1812PubMedCrossRef Rice JC, Massey-Brown KS, Futscher BW (1998) Aberrant methylation of the BRCA1 CpG island promoter is associated with decreased BRCA1 mRNA in sporadic breast cancer cells. Oncogene 17:1807–1812PubMedCrossRef
7.
go back to reference Esteller M, Silva JM, Dominguez G, Bonilla F, Matias-Guiu X, Lerma E et al (2000) Promoter hypermethylation and BRCA1 inactivation in sporadic breast and ovarian tumors. J Natl Cancer Inst 92:564–569PubMedCrossRef Esteller M, Silva JM, Dominguez G, Bonilla F, Matias-Guiu X, Lerma E et al (2000) Promoter hypermethylation and BRCA1 inactivation in sporadic breast and ovarian tumors. J Natl Cancer Inst 92:564–569PubMedCrossRef
8.
go back to reference Rice JC, Ozcelik H, Maxeiner P, Andrulis I, Futscher BW (2000) Methylation of the BRCA1 promoter is associated with decreased BRCA1 mRNA levels in clinical breast cancer specimens. Carcinogenesis 21:1761–1765PubMedCrossRef Rice JC, Ozcelik H, Maxeiner P, Andrulis I, Futscher BW (2000) Methylation of the BRCA1 promoter is associated with decreased BRCA1 mRNA levels in clinical breast cancer specimens. Carcinogenesis 21:1761–1765PubMedCrossRef
9.
go back to reference Birgisdottir V, Stefansson OA, Bodvarsdottir SK, Hilmarsdottir H, Jonasson JG, Eyfjord JE (2006) Epigenetic silencing and deletion of the BRCA1 gene in sporadic breast cancer. Breast Cancer Res 8:R38PubMedCrossRef Birgisdottir V, Stefansson OA, Bodvarsdottir SK, Hilmarsdottir H, Jonasson JG, Eyfjord JE (2006) Epigenetic silencing and deletion of the BRCA1 gene in sporadic breast cancer. Breast Cancer Res 8:R38PubMedCrossRef
10.
go back to reference Xu X, Gammon MD, Zhang Y, Bestor TH, Zeisel SH, Wetmur JG et al (2009) BRCA1 promoter methylation is associated with increased mortality among women with breast cancer. Breast Cancer Res Treat 115:397–404PubMedCrossRef Xu X, Gammon MD, Zhang Y, Bestor TH, Zeisel SH, Wetmur JG et al (2009) BRCA1 promoter methylation is associated with increased mortality among women with breast cancer. Breast Cancer Res Treat 115:397–404PubMedCrossRef
11.
go back to reference Rosen EM, Fan S, Pestell RG, Goldberg ID (2003) BRCA1 gene in breast cancer. J Cell Physiol 196:19–41PubMedCrossRef Rosen EM, Fan S, Pestell RG, Goldberg ID (2003) BRCA1 gene in breast cancer. J Cell Physiol 196:19–41PubMedCrossRef
12.
go back to reference Rebbeck TR, Levin AM, Eisen A, Synder C, Watson P, Cannon-Albright L et al (1999) Breast cancer risk after bilateral prophylactic oophorectomy in BRCA1 mutation carriers. J Natl Cancer Inst 91:1475–1479PubMedCrossRef Rebbeck TR, Levin AM, Eisen A, Synder C, Watson P, Cannon-Albright L et al (1999) Breast cancer risk after bilateral prophylactic oophorectomy in BRCA1 mutation carriers. J Natl Cancer Inst 91:1475–1479PubMedCrossRef
13.
go back to reference Armes JE, Trute L, White D, Southey MC, Hammet F, Tesoriero A et al (1999) Distinct molecular pathogeneses of early-onset breast cancers in BRCA1 and BRCA2 mutation carriers: a population-based study. Cancer Res 59:2011–2017PubMed Armes JE, Trute L, White D, Southey MC, Hammet F, Tesoriero A et al (1999) Distinct molecular pathogeneses of early-onset breast cancers in BRCA1 and BRCA2 mutation carriers: a population-based study. Cancer Res 59:2011–2017PubMed
14.
go back to reference Lakhani SR, Van De Vijever MJ, Jacquemier J, Anderson TJ, Osin PP, McGuffog L et al (2002) The pathology of familial breast cancer: predictive value of immunohistochemical markers estrogen receptor, progesterone receptor, HER-2, and p53 in patients with mutations in BRCA1 and BRCA2. J Clin Oncol 20:2310–2318PubMedCrossRef Lakhani SR, Van De Vijever MJ, Jacquemier J, Anderson TJ, Osin PP, McGuffog L et al (2002) The pathology of familial breast cancer: predictive value of immunohistochemical markers estrogen receptor, progesterone receptor, HER-2, and p53 in patients with mutations in BRCA1 and BRCA2. J Clin Oncol 20:2310–2318PubMedCrossRef
15.
go back to reference Hosey AM, Gorski JJ, Murray MM, Quinn JE, Chung WY, Stewart GE et al (2007) Molecular basis for estrogen receptor α deficiency in BRCA1-linked breast cancer. J Natl Cancer Inst 99:1683–1694PubMedCrossRef Hosey AM, Gorski JJ, Murray MM, Quinn JE, Chung WY, Stewart GE et al (2007) Molecular basis for estrogen receptor α deficiency in BRCA1-linked breast cancer. J Natl Cancer Inst 99:1683–1694PubMedCrossRef
16.
go back to reference Gorski JJ, Kennedy RD, Hosey AM, Harkin DP (2009) The complex relationship between BRCA1 and Erα in hereditary breast cancer. Clin Cancer Res 15:1514–1518PubMedCrossRef Gorski JJ, Kennedy RD, Hosey AM, Harkin DP (2009) The complex relationship between BRCA1 and Erα in hereditary breast cancer. Clin Cancer Res 15:1514–1518PubMedCrossRef
17.
go back to reference Li W, Xiao C, Vonderhaar BK, Deng CX (2007) A role of estrogen/ERα signaling in BRCA1-associated tissue-specific tumor formation. Oncogene 26:7204–7212PubMedCrossRef Li W, Xiao C, Vonderhaar BK, Deng CX (2007) A role of estrogen/ERα signaling in BRCA1-associated tissue-specific tumor formation. Oncogene 26:7204–7212PubMedCrossRef
18.
go back to reference Jones LP, Tilli MT, Assefnia S, Torre K, Halama ED, Parrish A et al (2008) Activation of estrogen signaling pathways collaborates with loss of BRCA1 to promote development of ERα-negative and ERα-positive mammary preneoplasia and cancer. Oncogene 27:794–802PubMedCrossRef Jones LP, Tilli MT, Assefnia S, Torre K, Halama ED, Parrish A et al (2008) Activation of estrogen signaling pathways collaborates with loss of BRCA1 to promote development of ERα-negative and ERα-positive mammary preneoplasia and cancer. Oncogene 27:794–802PubMedCrossRef
19.
go back to reference Metcalfe K, Lynch HT, Ghadirian P, Tung N, Olivotto I, Warner E et al (2004) Contralateral breast cancer in BRCA1 and BRCA2 mutation carriers. J Clin Oncol 22:2328–2335PubMedCrossRef Metcalfe K, Lynch HT, Ghadirian P, Tung N, Olivotto I, Warner E et al (2004) Contralateral breast cancer in BRCA1 and BRCA2 mutation carriers. J Clin Oncol 22:2328–2335PubMedCrossRef
20.
go back to reference Poole AJ, Li Y, Kim Y, Lin SC, Lee WH, Lee EY (2006) Prevention of BRCA1-mediated mammary tumorigenesis in mice by a progesterone antagonist. Science 314:1467–1470PubMedCrossRef Poole AJ, Li Y, Kim Y, Lin SC, Lee WH, Lee EY (2006) Prevention of BRCA1-mediated mammary tumorigenesis in mice by a progesterone antagonist. Science 314:1467–1470PubMedCrossRef
21.
go back to reference Jones LP, Li M, Halama ED, Ma Y, Lubet R, Grubbs CJ et al (2005) Promotion of mammary cancer development by tamoxifen in a mouse model of BRCA1-mutation-related breast cancer. Oncogene 24:3554–3562PubMedCrossRef Jones LP, Li M, Halama ED, Ma Y, Lubet R, Grubbs CJ et al (2005) Promotion of mammary cancer development by tamoxifen in a mouse model of BRCA1-mutation-related breast cancer. Oncogene 24:3554–3562PubMedCrossRef
22.
go back to reference King MC, Wieand S, Hale K, Lee M, Walsh T, Owens K et al (2001) Tamoxifen and breast cancer incidence among women with inherited mutations in BRCA1 and BRCA2. JAMA 286:2251–2256PubMedCrossRef King MC, Wieand S, Hale K, Lee M, Walsh T, Owens K et al (2001) Tamoxifen and breast cancer incidence among women with inherited mutations in BRCA1 and BRCA2. JAMA 286:2251–2256PubMedCrossRef
23.
go back to reference Beiner ME, Finch A, Rosen B, Lubinski J, Moller P, Ghadirian P et al (2007) The risk of endometrial cancer in women with BRCA1 and BRCA2 mutations. A prospective study. Gynecol Oncol 104:7–10PubMedCrossRef Beiner ME, Finch A, Rosen B, Lubinski J, Moller P, Ghadirian P et al (2007) The risk of endometrial cancer in women with BRCA1 and BRCA2 mutations. A prospective study. Gynecol Oncol 104:7–10PubMedCrossRef
24.
go back to reference Lu KH, Kauff ND (2007) Does a BRCA mutation plus tamoxifen equal hysterectomy? Gynecol Oncol 104:3–4PubMedCrossRef Lu KH, Kauff ND (2007) Does a BRCA mutation plus tamoxifen equal hysterectomy? Gynecol Oncol 104:3–4PubMedCrossRef
25.
go back to reference Wen J, Li R, Lu Y, Shupnik MA (2009) Decreased BRCA1 confers tamoxifen resistance in breast cancer cells by altering estrogen receptor-coregulator interactions. Oncogene 28:575–586PubMedCrossRef Wen J, Li R, Lu Y, Shupnik MA (2009) Decreased BRCA1 confers tamoxifen resistance in breast cancer cells by altering estrogen receptor-coregulator interactions. Oncogene 28:575–586PubMedCrossRef
26.
go back to reference Pathiraja TN, Shetty PB, Jelinek J, He R, Hartmaier R, Margossian AL et al (2011) Progesterone receptor isoform-specific promoter methylation: association of PRA promoter methylation with worse outcome in breast cancer patients. Clin Cancer Res 17:4177–4186PubMedCrossRef Pathiraja TN, Shetty PB, Jelinek J, He R, Hartmaier R, Margossian AL et al (2011) Progesterone receptor isoform-specific promoter methylation: association of PRA promoter methylation with worse outcome in breast cancer patients. Clin Cancer Res 17:4177–4186PubMedCrossRef
27.
go back to reference Colella S, Shen L, Baggerly KA, Issa JP, Krahe R (2003) Sensitive and quantitative universal pyrosequencing methylation analysis of CpG sites. Biotechniques 35:146–150PubMed Colella S, Shen L, Baggerly KA, Issa JP, Krahe R (2003) Sensitive and quantitative universal pyrosequencing methylation analysis of CpG sites. Biotechniques 35:146–150PubMed
28.
go back to reference Hilsenbeck SG, Clark GM (1996) Practical p-value adjustment for optimally selected cutpoints. Stat Med 15:103–112PubMedCrossRef Hilsenbeck SG, Clark GM (1996) Practical p-value adjustment for optimally selected cutpoints. Stat Med 15:103–112PubMedCrossRef
29.
go back to reference Fisher B, Costantino J, Redmond C, Poisson R, Bowman D, Couture J et al (1989) A randomized clinical trial evaluating tamoxifen in the treatment of patients with node-negative breast cancer who have estroge-receptor-positive tumors. N Engl J Med 320:479–484PubMedCrossRef Fisher B, Costantino J, Redmond C, Poisson R, Bowman D, Couture J et al (1989) A randomized clinical trial evaluating tamoxifen in the treatment of patients with node-negative breast cancer who have estroge-receptor-positive tumors. N Engl J Med 320:479–484PubMedCrossRef
30.
go back to reference Clarke R, Liu MC, Bouker KB, Gu Z, Lee RY, Zhu Y et al (2003) Antiestrogen resistance in breast cancer and the role of estrogen receptor signaling. Oncogene 22:7316–7339PubMedCrossRef Clarke R, Liu MC, Bouker KB, Gu Z, Lee RY, Zhu Y et al (2003) Antiestrogen resistance in breast cancer and the role of estrogen receptor signaling. Oncogene 22:7316–7339PubMedCrossRef
31.
go back to reference Xu CF, Chambers JA, Solomon E (1997) Complex regulation of the BRCA1 gene. J Biol Chem 272:20994–20997PubMedCrossRef Xu CF, Chambers JA, Solomon E (1997) Complex regulation of the BRCA1 gene. J Biol Chem 272:20994–20997PubMedCrossRef
32.
33.
go back to reference Fiegl H, Millinger S, Mueller-Holzner E, Marth C, Ensinger C, Berger A et al (2005) Circulating tumor-specific DNA: a marker for monitoring efficacy of adjuvant therapy in cancer patients. Cancer Res 65:1141–1145PubMedCrossRef Fiegl H, Millinger S, Mueller-Holzner E, Marth C, Ensinger C, Berger A et al (2005) Circulating tumor-specific DNA: a marker for monitoring efficacy of adjuvant therapy in cancer patients. Cancer Res 65:1141–1145PubMedCrossRef
34.
go back to reference Wilcox CB, Baysal BE, Gallion HH, Strange MA, DeLoia JA (2005) High-resolution methylation analysis of the BRCA1 promoter in ovarian tumors. Cancer Genet Cytogenet 159:114–122PubMedCrossRef Wilcox CB, Baysal BE, Gallion HH, Strange MA, DeLoia JA (2005) High-resolution methylation analysis of the BRCA1 promoter in ovarian tumors. Cancer Genet Cytogenet 159:114–122PubMedCrossRef
35.
go back to reference Catteau A, Morris JR (2002) BRCA1 methylation: a significant role in tumor development? Semin Cancer Biol 12:359–371PubMedCrossRef Catteau A, Morris JR (2002) BRCA1 methylation: a significant role in tumor development? Semin Cancer Biol 12:359–371PubMedCrossRef
36.
go back to reference Wei M, Grushko TA, Dignam J, Hagos F, Nanda R, Sveen L et al (2005) BRCA1 promoter methylation in sporadic breast cancer is associated with reduced BRCA1 copy number and chromosome 17 aneusomy. Cancer Res 65:10692–10699PubMedCrossRef Wei M, Grushko TA, Dignam J, Hagos F, Nanda R, Sveen L et al (2005) BRCA1 promoter methylation in sporadic breast cancer is associated with reduced BRCA1 copy number and chromosome 17 aneusomy. Cancer Res 65:10692–10699PubMedCrossRef
37.
go back to reference Jin W, Liu Y, Chen L, Zhu H, Di GH, Ling H et al (2011) Involvement of MyoD and c-myb in regulation of basal and estrogen-induced transcriptional activity of the BRCA1 gene. Breast Cancer Res Treat 125:699–713PubMedCrossRef Jin W, Liu Y, Chen L, Zhu H, Di GH, Ling H et al (2011) Involvement of MyoD and c-myb in regulation of basal and estrogen-induced transcriptional activity of the BRCA1 gene. Breast Cancer Res Treat 125:699–713PubMedCrossRef
38.
go back to reference Xu J, Huo D, Chen Y, Nwachukwu C, Collins C, Rowell et al (2010) CpG methylation affects accessibility of the proximal BRCA1 promoter to transcription factors. Breast Cancer Res Treat 120:593–601PubMedCrossRef Xu J, Huo D, Chen Y, Nwachukwu C, Collins C, Rowell et al (2010) CpG methylation affects accessibility of the proximal BRCA1 promoter to transcription factors. Breast Cancer Res Treat 120:593–601PubMedCrossRef
Metadata
Title
BRCA1 promoter methylation status does not predict response to tamoxifen in sporadic breast cancer patients
Authors
Jasmina Z. Cerne
Lin Zong
Jaroslav Jelinek
Susan G. Hilsenbeck
Tao Wang
Steffi Oesterreich
Sean E. McGuire
Publication date
01-08-2012
Publisher
Springer US
Published in
Breast Cancer Research and Treatment / Issue 1/2012
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI
https://doi.org/10.1007/s10549-012-2117-2

Other articles of this Issue 1/2012

Breast Cancer Research and Treatment 1/2012 Go to the issue
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine