Clinical significance of Stratifin, ERalpha and PR promoter methylation in tumor and serum DNA in Indian breast cancer patients.

OBJECTIVES The objective of this study was to determine the concordance of promoter methylation of stratifin, ERalpha and PR in tumor and circulating DNA in breast cancer patients and their association with clinicopathological parameters and disease prognosis. DESIGN AND METHODS Methylation specific PCR were carried out to investigate the promoter methylation status of stratifin, ERalpha and PR in tumor and circulating DNA in 100 breast cancer patients in a prospective study. The effect of promoter methylation on protein expression was evaluated by immunohistochemistry. RESULTS Significant association was observed between promoter methylation of stratifin in tumors (61%) and paired sera (56%) (r=0.78; p < or = 0.001). Loss of stratifin expression was observed in 47% tumors and was associated with poor overall survival (p=0.05). Significant correlation was observed between methylation status of ERalpha with PRB (p<0.0001, OR=20.8, 95% CI=7.4-58.0) and stratifin (p=0.003, OR=2.0, 95% CI=0.8-4.4). CONCLUSION This study underscores the potential utility of serum DNA methylation of these genes as surrogate for tumor DNA methylation as a promising tool for cancer diagnosis.

[1]  T. Nakajima,et al.  Immunohistochemical analysis of 14‐3‐3 sigma and related proteins in hyperplastic and neoplastic breast lesions, with particular reference to early carcinogenesis , 2004, Pathology international.

[2]  M. Esteller.  Aberrant DNA methylation as a cancer-inducing mechanism. , 2005, Annual review of pharmacology and toxicology.

[3]  K. Kinzler,et al.  Cooperative effects of genes controlling the G(2)/M checkpoint. , 2000, Genes & development.

[4]  Mong-Hong Lee,et al.  Association of the Cyclin-dependent Kinases and 14-3-3 Sigma Negatively Regulates Cell Cycle Progression* , 2000, The Journal of Biological Chemistry.

[5]  P. Laird.  Early detection: The power and the promise of DNA methylation markers , 2003, Nature Reviews Cancer.

[6]  T. Pandita,et al.  High frequency of hypermethylation at the 14-3-3 sigma locus leads to gene silencing in breast cancer. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[7]  S. Sukumar,et al.  Hypermethylation of 14-3-3 σ (stratifin) is an early event in breast cancer , 2001, Oncogene.

[8]  Xin Hu,et al.  Correlation between CpG methylation profiles and hormone receptor status in breast cancers , 2007, Breast Cancer Research.

[9]  Hiromu Suzuki,et al.  Frequent hypermethylation of CpG islands and loss of expression of the 14-3-3 σ gene in human hepatocellular carcinoma , 2000, Oncogene.

[10]  Anthony Rhodes,et al.  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. , 2002, American journal of clinical pathology.

[11]  J. Ferlay,et al.  Global Cancer Statistics, 2002 , 2005, CA: a cancer journal for clinicians.

[12]  Mong-Hong Lee,et al.  14-3-3 sigma positively regulates p53 and suppresses tumor growth. , 2003, Molecular and cellular biology.

[13]  J. Minna,et al.  Promoter hypermethylation in benign breast epithelium in relation to predicted breast cancer risk. , 2005, Clinical cancer research : an official journal of the American Association for Cancer Research.

[14]  B. White,et al.  The Micro-Ribonucleic Acid (miRNA) miR-206 Targets the Human Estrogen Receptor-α (ERα) and Represses ERα Messenger RNA and Protein Expression in Breast Cancer Cell Lines , 2007 .

[15]  Chintamani,et al.  Clinico-morphological patterns of breast cancer including family history in a New Delhi hospital, India-A cross-sectional study , 2005, World journal of surgical oncology.

[16]  L. Sobin,et al.  TNM classification of malignant tumors, fifth edition (1997) , 1997, Cancer.

[17]  S. Mirza,et al.  Promoter hypermethylation of TMS1, BRCA1, ERalpha and PRB in serum and tumor DNA of invasive ductal breast carcinoma patients. , 2007, Life sciences.

[18]  L. E. McDonald,et al.  A genomic sequencing protocol that yields a positive display of 5-methylcytosine residues in individual DNA strands. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[19]  B. Gusterson,et al.  Epigenetic inactivation of 14-3-3 sigma in oral carcinoma: association with p16(INK4a) silencing and human papillomavirus negativity. , 2002, Cancer research.

[20]  G. Greene,et al.  Immunocytochemical estrogen and progestin receptor assays in breast cancer with monoclonal antibodies. Histopathologic, demographic, and biochemical correlations and relationship to endocrine response and survival , 1990, Cancer.

[21]  R Chopra,et al.  The Indian Scene , 1955, Oryx.

[22]  B. White,et al.  The micro-ribonucleic acid (miRNA) miR-206 targets the human estrogen receptor-alpha (ERalpha) and represses ERalpha messenger RNA and protein expression in breast cancer cell lines. , 2007, Molecular endocrinology.

[23]  T. Schlott,et al.  Promoter hypermethylation of the 14-3-3 sigma, SYK and CAGE-1 genes is related to the various phenotypes of urinary bladder carcinomas and associated with progression of transitional cell carcinomas. , 2006, International journal of molecular medicine.

[24]  S. Inoue,et al.  Decreased expression of 14-3-3 sigma is associated with advanced disease in human epithelial ovarian cancer: its correlation with aberrant DNA methylation. , 2004, Clinical cancer research : an official journal of the American Association for Cancer Research.

[25]  M. Szyf,et al.  DNA methylation and breast cancer. , 2004, Biochemical pharmacology.

[26]  M. Villalobos,et al.  Quantitative detection of methylated ESR1 and 14-3-3-σ gene promoters in serum as candidate biomarkers for diagnosis of breast cancer and evaluation of treatment efficacy , 2008, Cancer biology & therapy.

[27]  Mong-Hong Lee,et al.  14-3-3σ Positively Regulates p53 and Suppresses Tumor Growth , 2003, Molecular and Cellular Biology.

[28]  Martin Widschwendter,et al.  Circulating tumor-specific DNA: a marker for monitoring efficacy of adjuvant therapy in cancer patients. , 2005, Cancer research.

[29]  A. Fabiato,et al.  Anonymity of reviewers , 1994 .

[30]  S. Sukumar,et al.  Hypermethylation of 14-3-3 sigma (stratifin) is an early event in breast cancer. , 2001, Oncogene.

[31]  A. Giuliano,et al.  Distinct Hypermethylation Profile of Primary Breast Cancer Is Associated with Sentinel Lymph Node Metastasis , 2005, Clinical Cancer Research.

[32]  R. Dahiya,et al.  Progesterone receptor B gene inactivation and CpG hypermethylation in human uterine endometrial cancer. , 2001, Cancer research.

[33]  S. Weitzman,et al.  Methylation of estrogen and progesterone receptor gene 5' CpG islands correlates with lack of estrogen and progesterone receptor gene expression in breast tumors. , 1996, Clinical cancer research : an official journal of the American Association for Cancer Research.

[34]  Y. Yatabe,et al.  Frequent and histological type-specific inactivation of 14-3-3σ in human lung cancers , 2002, Oncogene.

[35]  Anurag Srivastava,et al.  Promoter hypermethylation of p16INK4A, p14ARF, CyclinD2 and Slit2 in serum and tumor DNA from breast cancer patients. , 2007, Life sciences.

[36]  M. Toyota,et al.  Inactivation of the 14-3-3 sigma gene is associated with 5' CpG island hypermethylation in human cancers. , 2000, Cancer research.

[37]  Peter A. Jones,et al.  Epigenetics in cancer. , 2010, Carcinogenesis.

[38]  A. Balmain,et al.  A Mouse Skin Multistage Carcinogenesis Model Reflects the Aberrant DNA Methylation Patterns of Human Tumors , 2004, Cancer Research.

[39]  A. Carvalho,et al.  Frequent 14-3-3 sigma promoter methylation in benign and malignant prostate lesions. , 2005, DNA and cell biology.

[40]  Victor X Jin,et al.  Loss of Estrogen Receptor Signaling Triggers Epigenetic Silencing of Downstream Targets in Breast Cancer , 2004, Cancer Research.

[41]  A. Giordano,et al.  Epigenetic information and estrogen receptor alpha expression in breast cancer. , 2006, The oncologist.

[42]  A. Carvalho,et al.  Frequent 14-3-3σ promoter methylation in benign and malignant prostate lesions , 2005 .

[43]  Christopher B Umbricht,et al.  Detection of breast cancer cells in ductal lavage fluid by methylation-specific PCR , 2001, The Lancet.