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Erschienen in: Annals of Surgical Oncology 9/2012

01.09.2012 | Translational Research and Biomarkers

Clinical Significance of Promoter Hypermethylation of ERβ and RARβ2 in Tumor and Serum DNA in Indian Breast Cancer Patients

verfasst von: Sameer Mirza, PhD, Gayatri Sharma, PhD, Rajinder Parshad, MS, Anurag Srivastava, MS, Siddartha Datta Gupta, MD, Ranju Ralhan, PhD

Erschienen in: Annals of Surgical Oncology | Ausgabe 9/2012

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Abstract

Purpose

To determine concordance of promoter hypermethylation of ERβ (estrogen receptor β) and RARβ2 (retinoic acid receptor β2) in tumor and circulating DNA of Indian breast cancer patients and their association with clinicopathologic parameters and disease prognosis.

Methods

ERβ and RARβ2 methylation was analyzed by methylation-specific PCR in the tumors and circulating DNA of 100 patients with invasive ductal breast carcinoma. Promoter hypermethylation was associated with the expression of the encoded protein in tumors by immunohistochemistry, and their prognostic utility was explored in a follow-up study.

Results

Significant correlation was observed between promoter hypermethylation of ERβ (r = + 0.77; p ≤ 0.001) and RARβ2 (r = + 0.85; p ≤ 0.001) in tumors and paired sera. No association was found between ERβ and RARβ2 promoter hypermethylation and loss of protein expression. Kaplan–Meier survival curve showed loss of ERβ expression, and RARβ2 promoter hypermethylation was associated with poor overall survival (OS) (p = 0.03, p = 0.001). Breast cancer patients showing concurrent hypermethylation of ERβ and RARβ2 had a significantly shorter median OS (p = 0.02), underscoring that hypermethylation of these two genes may serve as an adverse prognosticator for breast carcinoma.

Conclusions

Methylation status of ERβ and RARβ2 in serum could potentially be used to predict invasive ductal breast carcinoma. Furthermore, concurrent ERβ and RARβ2 methylation as well as loss of ERβ expression may serve as a good prognostic marker.
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Literatur
1.
Zurück zum Zitat Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin. 2005;55:74–108.PubMedCrossRef Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin. 2005;55:74–108.PubMedCrossRef
3.
Zurück zum Zitat Esteller M, Corn PG, Baylin SB, Herman JG. A gene hypermethylation profile of human cancer. Cancer Res. 2001;61:3225–9.PubMed Esteller M, Corn PG, Baylin SB, Herman JG. A gene hypermethylation profile of human cancer. Cancer Res. 2001;61:3225–9.PubMed
4.
Zurück zum Zitat Dulaimi E, Hillinck J, Ibanez de Caceres I, Al-Saleem T, Cairns P. Tumor suppressor gene promoter hypermethylation in serum of breast cancer patients. Clin Cancer Res. 2004;15:6189–93.CrossRef Dulaimi E, Hillinck J, Ibanez de Caceres I, Al-Saleem T, Cairns P. Tumor suppressor gene promoter hypermethylation in serum of breast cancer patients. Clin Cancer Res. 2004;15:6189–93.CrossRef
5.
Zurück zum Zitat Leon SA, Shapiro B, Sklaroff DM, Yaros MJ. Free DNA in the serum of cancer patients and the effect of therapy. Cancer Res. 1977;37:646–50.PubMed Leon SA, Shapiro B, Sklaroff DM, Yaros MJ. Free DNA in the serum of cancer patients and the effect of therapy. Cancer Res. 1977;37:646–50.PubMed
6.
Zurück zum Zitat Dechering K, Boersma C, Mosselman S. Estrogen receptors alpha and beta: two receptors of a kind? Curr Med Chem. 2000;7:561–76.PubMed Dechering K, Boersma C, Mosselman S. Estrogen receptors alpha and beta: two receptors of a kind? Curr Med Chem. 2000;7:561–76.PubMed
7.
Zurück zum Zitat Lazennec G, Bresson D, Lucas A, Chauveau C, Vignon F. ER beta inhibits proliferation and invasion of breast cancer cells. Endocrinology. 2001;142:4120–30.PubMedCrossRef Lazennec G, Bresson D, Lucas A, Chauveau C, Vignon F. ER beta inhibits proliferation and invasion of breast cancer cells. Endocrinology. 2001;142:4120–30.PubMedCrossRef
8.
Zurück zum Zitat Jarvinen TA, Pelto-Huikko M, Holli K, Isola J. Estrogen receptor beta is coexpressed with ERalpha and PR and associated with nodal status, grade, and proliferation rate in breast cancer. Am J Pathol. 2000;156:29–35.PubMedCrossRef Jarvinen TA, Pelto-Huikko M, Holli K, Isola J. Estrogen receptor beta is coexpressed with ERalpha and PR and associated with nodal status, grade, and proliferation rate in breast cancer. Am J Pathol. 2000;156:29–35.PubMedCrossRef
9.
Zurück zum Zitat Speirs V, Parkes AT, Kerin MJ, et al. Coexpression of estrogen receptor alpha and beta: poor prognostic factors in human breast cancer? Cancer Res. 1999;59:525–8.PubMed Speirs V, Parkes AT, Kerin MJ, et al. Coexpression of estrogen receptor alpha and beta: poor prognostic factors in human breast cancer? Cancer Res. 1999;59:525–8.PubMed
10.
Zurück zum Zitat Clarke N, Germain P, Altucci L, Gronemeyer H. Retinoids: potential in cancer prevention and therapy. Expert Rev Mol Med. 2004;6:1–23.PubMedCrossRef Clarke N, Germain P, Altucci L, Gronemeyer H. Retinoids: potential in cancer prevention and therapy. Expert Rev Mol Med. 2004;6:1–23.PubMedCrossRef
11.
Zurück zum Zitat Lewis CM, Cler LR, Bu DW, et al. Promoter hypermethylation in benign breast epithelium in relation to predicted breast cancer risk. Clin Cancer Res. 2005;11:166–72.PubMed Lewis CM, Cler LR, Bu DW, et al. Promoter hypermethylation in benign breast epithelium in relation to predicted breast cancer risk. Clin Cancer Res. 2005;11:166–72.PubMed
12.
Zurück zum Zitat Frommer M, McDonald LE, Millar DS, et al. A genomic sequencing protocol that yields a positive display of 5-methylcytosine residues in individual DNA strands. Proc Natl Acad Sci USA. 1992;89:1827–31.PubMedCrossRef Frommer M, McDonald LE, Millar DS, et al. A genomic sequencing protocol that yields a positive display of 5-methylcytosine residues in individual DNA strands. Proc Natl Acad Sci USA. 1992;89:1827–31.PubMedCrossRef
13.
Zurück zum Zitat Sasaki M, Kotcherguina L, Dharia A, Fujimoto S, Dahiya R. Cytosine-phosphoguanine methylation of estrogen receptors in endometrial cancer. Cancer Res. 2001;61:3262–6.PubMed Sasaki M, Kotcherguina L, Dharia A, Fujimoto S, Dahiya R. Cytosine-phosphoguanine methylation of estrogen receptors in endometrial cancer. Cancer Res. 2001;61:3262–6.PubMed
14.
Zurück zum Zitat Virmani AK, Rathi A, Zochbauer-Muller S, et al. Promoter methylation and silencing of the retinoic acid receptor-beta gene in lung carcinomas. J Natl Cancer Inst. 2000;92:1303–7.PubMedCrossRef Virmani AK, Rathi A, Zochbauer-Muller S, et al. Promoter methylation and silencing of the retinoic acid receptor-beta gene in lung carcinomas. J Natl Cancer Inst. 2000;92:1303–7.PubMedCrossRef
15.
Zurück zum Zitat Mirza S, Sharma G, Prasad CP, et al. Promoter hypermethylation of TMS1, BRCA1, ERalpha and PRB in serum and tumor DNA of invasive ductal breast carcinoma patients. Life Sci. 2007;81:280–7.PubMedCrossRef Mirza S, Sharma G, Prasad CP, et al. Promoter hypermethylation of TMS1, BRCA1, ERalpha and PRB in serum and tumor DNA of invasive ductal breast carcinoma patients. Life Sci. 2007;81:280–7.PubMedCrossRef
16.
Zurück zum Zitat Goldhirsch A, Wood WC, Gelber RD, Coates AS, Thurlimann B, Senn HJ. Meeting highlights: updated international expert consensus on the primary therapy of early breast cancer. J Clin Oncol. 2003;21:3357–65.PubMedCrossRef Goldhirsch A, Wood WC, Gelber RD, Coates AS, Thurlimann B, Senn HJ. Meeting highlights: updated international expert consensus on the primary therapy of early breast cancer. J Clin Oncol. 2003;21:3357–65.PubMedCrossRef
17.
Zurück zum Zitat Mann S, Laucirica R, Carlson N, et al. Estrogen receptor beta expression in invasive breast cancer. Hum Pathol. 2001;32:113–8.PubMedCrossRef Mann S, Laucirica R, Carlson N, et al. Estrogen receptor beta expression in invasive breast cancer. Hum Pathol. 2001;32:113–8.PubMedCrossRef
18.
Zurück zum Zitat Nakopoulou L, Lazaris AC, Panayotopoulou EG, et al. The favourable prognostic value of oestrogen receptor beta immunohistochemical expression in breast cancer. J Clin Pathol. 2004;57:523–8.PubMedCrossRef Nakopoulou L, Lazaris AC, Panayotopoulou EG, et al. The favourable prognostic value of oestrogen receptor beta immunohistochemical expression in breast cancer. J Clin Pathol. 2004;57:523–8.PubMedCrossRef
19.
Zurück zum Zitat Rhodes A, Jasani B, Anderson E, Dodson AR, Balaton AJ. Evaluation of HER-2/neu immunohistochemical assay sensitivity and scoring on formalin-fixed and paraffin-processed cell lines and breast tumors: a comparative study involving results from laboratories in 21 countries. Am J Clin Pathol. 2002;118:408–17.PubMedCrossRef Rhodes A, Jasani B, Anderson E, Dodson AR, Balaton AJ. Evaluation of HER-2/neu immunohistochemical assay sensitivity and scoring on formalin-fixed and paraffin-processed cell lines and breast tumors: a comparative study involving results from laboratories in 21 countries. Am J Clin Pathol. 2002;118:408–17.PubMedCrossRef
20.
Zurück zum Zitat Sharma G, Mirza S, Yang YH, et al. Prognostic relevance of promoter hypermethylation of multiple genes in breast cancer patients. Cell Oncol. 2009;31:487–500.PubMed Sharma G, Mirza S, Yang YH, et al. Prognostic relevance of promoter hypermethylation of multiple genes in breast cancer patients. Cell Oncol. 2009;31:487–500.PubMed
21.
Zurück zum Zitat Sharma G, Mirza S, Parshad R, et al. CpG hypomethylation of MDR1 gene in tumor and serum of invasive ductal breast carcinoma patients. Clin Biochem. 2010;43:373–9.PubMedCrossRef Sharma G, Mirza S, Parshad R, et al. CpG hypomethylation of MDR1 gene in tumor and serum of invasive ductal breast carcinoma patients. Clin Biochem. 2010;43:373–9.PubMedCrossRef
22.
Zurück zum Zitat Sharma G, Mirza S, Parshad R, et al. Clinical significance of promoter hypermethylation of DNA repair genes in tumor and serum DNA in invasive ductal breast carcinoma patients. Life Sci. 2010;87:83–91.PubMedCrossRef Sharma G, Mirza S, Parshad R, et al. Clinical significance of promoter hypermethylation of DNA repair genes in tumor and serum DNA in invasive ductal breast carcinoma patients. Life Sci. 2010;87:83–91.PubMedCrossRef
23.
Zurück zum Zitat Mirza S, Sharma G, Parshad R, Srivastava A, Gupta SD, Ralhan R. Clinical significance of stratifin, ERalpha and PR promoter methylation in tumor and serum DNA in Indian breast cancer patients. Clin Biochem. 2010;43:380–6.PubMedCrossRef Mirza S, Sharma G, Parshad R, Srivastava A, Gupta SD, Ralhan R. Clinical significance of stratifin, ERalpha and PR promoter methylation in tumor and serum DNA in Indian breast cancer patients. Clin Biochem. 2010;43:380–6.PubMedCrossRef
24.
Zurück zum Zitat Saxena S, Rekhi B, Bansal A, Bagga A, Chintamani, Murthy NS. Clinico-morphological patterns of breast cancer including family history in a New Delhi hospital, India—a cross-sectional study. World J Surg Oncol. 2005;3:67.PubMedCrossRef Saxena S, Rekhi B, Bansal A, Bagga A, Chintamani, Murthy NS. Clinico-morphological patterns of breast cancer including family history in a New Delhi hospital, India—a cross-sectional study. World J Surg Oncol. 2005;3:67.PubMedCrossRef
25.
Zurück zum Zitat Speirs V, Skliris GP, Burdall SE, Carder PJ. Distinct expression patterns of ER alpha and ER beta in normal human mammary gland. J Clin Pathol. 2002;55:371–4.PubMedCrossRef Speirs V, Skliris GP, Burdall SE, Carder PJ. Distinct expression patterns of ER alpha and ER beta in normal human mammary gland. J Clin Pathol. 2002;55:371–4.PubMedCrossRef
26.
Zurück zum Zitat Treeck O, Lattrich C, Springwald A, Ortmann O. Estrogen receptor beta exerts growth-inhibitory effects on human mammary epithelial cells. Breast Cancer Res Treat. 2010;120:557–65.PubMedCrossRef Treeck O, Lattrich C, Springwald A, Ortmann O. Estrogen receptor beta exerts growth-inhibitory effects on human mammary epithelial cells. Breast Cancer Res Treat. 2010;120:557–65.PubMedCrossRef
27.
Zurück zum Zitat Skliris GP, Munot K, Bell SM, et al. Reduced expression of oestrogen receptor beta in invasive breast cancer and its re-expression using DNA methyl transferase inhibitors in a cell line model. J Pathol. 2003;201:213–20.PubMedCrossRef Skliris GP, Munot K, Bell SM, et al. Reduced expression of oestrogen receptor beta in invasive breast cancer and its re-expression using DNA methyl transferase inhibitors in a cell line model. J Pathol. 2003;201:213–20.PubMedCrossRef
28.
Zurück zum Zitat Al-Nakhle H, Burns PA, Cummings M, et al. Estrogen receptor {beta}1 expression is regulated by miR-92 in breast cancer. Cancer Res. 2010;70:4778–84.PubMedCrossRef Al-Nakhle H, Burns PA, Cummings M, et al. Estrogen receptor {beta}1 expression is regulated by miR-92 in breast cancer. Cancer Res. 2010;70:4778–84.PubMedCrossRef
29.
Zurück zum Zitat Mehrotra J, Vali M, McVeigh M, et al. Very high frequency of hypermethylated genes in breast cancer metastasis to the bone, brain, and lung. Clin Cancer Res. 2004;10:3104–9.PubMedCrossRef Mehrotra J, Vali M, McVeigh M, et al. Very high frequency of hypermethylated genes in breast cancer metastasis to the bone, brain, and lung. Clin Cancer Res. 2004;10:3104–9.PubMedCrossRef
30.
Zurück zum Zitat Shinozaki M, Hoon DS, Giuliano AE, et al. Distinct hypermethylation profile of primary breast cancer is associated with sentinel lymph node metastasis. Clin Cancer Res. 2005;11:2156–62.PubMedCrossRef Shinozaki M, Hoon DS, Giuliano AE, et al. Distinct hypermethylation profile of primary breast cancer is associated with sentinel lymph node metastasis. Clin Cancer Res. 2005;11:2156–62.PubMedCrossRef
31.
Zurück zum Zitat Li S, Rong M, Iacopetta B. DNA hypermethylation in breast cancer and its association with clinicopathological features. Cancer Lett. 2006;237:272–80.PubMedCrossRef Li S, Rong M, Iacopetta B. DNA hypermethylation in breast cancer and its association with clinicopathological features. Cancer Lett. 2006;237:272–80.PubMedCrossRef
32.
Zurück zum Zitat Feng W, Shen L, Wen S, et al. Correlation between CpG methylation profiles and hormone receptor status in breast cancers. Breast Cancer Res. 2007;9:R57.PubMedCrossRef Feng W, Shen L, Wen S, et al. Correlation between CpG methylation profiles and hormone receptor status in breast cancers. Breast Cancer Res. 2007;9:R57.PubMedCrossRef
33.
Zurück zum Zitat Deng G, Lu Y, Zlotnikov G, Thor AD, Smith HS. Loss of heterozygosity in normal tissue adjacent to breast carcinomas. Science. 1996;274:2057–9.PubMedCrossRef Deng G, Lu Y, Zlotnikov G, Thor AD, Smith HS. Loss of heterozygosity in normal tissue adjacent to breast carcinomas. Science. 1996;274:2057–9.PubMedCrossRef
34.
Zurück zum Zitat Widschwendter M, Berger J, Daxenbichler G, et al. Loss of retinoic acid receptor beta expression in breast cancer and morphologically normal adjacent tissue but not in the normal breast tissue distant from the cancer. Cancer Res. 1997;57:4158–61.PubMed Widschwendter M, Berger J, Daxenbichler G, et al. Loss of retinoic acid receptor beta expression in breast cancer and morphologically normal adjacent tissue but not in the normal breast tissue distant from the cancer. Cancer Res. 1997;57:4158–61.PubMed
35.
Zurück zum Zitat Sirchia SM, Ferguson AT, Sironi E, et al. Evidence of epigenetic changes affecting the chromatin state of the retinoic acid receptor beta2 promoter in breast cancer cells. Oncogene. 2000;19:1556–63.PubMedCrossRef Sirchia SM, Ferguson AT, Sironi E, et al. Evidence of epigenetic changes affecting the chromatin state of the retinoic acid receptor beta2 promoter in breast cancer cells. Oncogene. 2000;19:1556–63.PubMedCrossRef
36.
Zurück zum Zitat Widschwendter M, Berger J, Hermann M, et al. Methylation and silencing of the retinoic acid receptor-beta2 gene in breast cancer. J Natl Cancer Inst. 2000;92:826–32.PubMedCrossRef Widschwendter M, Berger J, Hermann M, et al. Methylation and silencing of the retinoic acid receptor-beta2 gene in breast cancer. J Natl Cancer Inst. 2000;92:826–32.PubMedCrossRef
37.
Zurück zum Zitat Subbaramaiah K, Cole PA, Dannenberg AJ. Retinoids and carnosol suppress cyclooxygenase-2 transcription by CREB-binding protein/p300-dependent and -independent mechanisms. Cancer Res. 2002;62:2522–30.PubMed Subbaramaiah K, Cole PA, Dannenberg AJ. Retinoids and carnosol suppress cyclooxygenase-2 transcription by CREB-binding protein/p300-dependent and -independent mechanisms. Cancer Res. 2002;62:2522–30.PubMed
38.
Zurück zum Zitat Rousseau C, Pettersson F, Couture MC, et al. The N-terminal of the estrogen receptor (ERalpha) mediates transcriptional cross-talk with the retinoic acid receptor in human breast cancer cells. J Steroid Biochem Mol Biol. 2003;86:1–14.PubMedCrossRef Rousseau C, Pettersson F, Couture MC, et al. The N-terminal of the estrogen receptor (ERalpha) mediates transcriptional cross-talk with the retinoic acid receptor in human breast cancer cells. J Steroid Biochem Mol Biol. 2003;86:1–14.PubMedCrossRef
39.
Zurück zum Zitat Rousseau C, Nichol JN, Pettersson F, Couture MC, Miller WH Jr. ERbeta sensitizes breast cancer cells to retinoic acid: evidence of transcriptional crosstalk. Mol Cancer Res. 2004;2:523–31.PubMed Rousseau C, Nichol JN, Pettersson F, Couture MC, Miller WH Jr. ERbeta sensitizes breast cancer cells to retinoic acid: evidence of transcriptional crosstalk. Mol Cancer Res. 2004;2:523–31.PubMed
Metadaten
Titel
Clinical Significance of Promoter Hypermethylation of ERβ and RARβ2 in Tumor and Serum DNA in Indian Breast Cancer Patients
verfasst von
Sameer Mirza, PhD
Gayatri Sharma, PhD
Rajinder Parshad, MS
Anurag Srivastava, MS
Siddartha Datta Gupta, MD
Ranju Ralhan, PhD
Publikationsdatum
01.09.2012
Verlag
Springer-Verlag
Erschienen in
Annals of Surgical Oncology / Ausgabe 9/2012
Print ISSN: 1068-9265
Elektronische ISSN: 1534-4681
DOI
https://doi.org/10.1245/s10434-012-2323-5

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