Estrogen receptor and HER2/neu status affect epigenetic differences of tumor-related genes in primary breast tumors

Eiji Sunami¹ , Masaru Shinozaki¹ , Myung-Shin Sim² , Sandy L Nguyen¹ , Anh-Thu Vu¹ , Armando E Giuliano³ and Dave SB Hoon¹

¹Department of Molecular Oncology, The John Wayne Cancer Institute, Saint John's Health Center, Santa Monica Blvd, Santa Monica, California 90404, USA

²Department of Biostatistics, The John Wayne Cancer Institute, Saint John's Health Center, Santa Monica Blvd, Santa Monica, California 90404, USA

³Department of Surgical Oncology, The John Wayne Cancer Institute, Saint John's Health Center, Santa Monica Blvd, Santa Monica, California 90404, USA

author email corresponding author email

Breast Cancer Research 2008, 10:R46doi:10.1186/bcr2098


Published:	16 May 2008

Abstract

Introduction

Estrogen receptor (ER)-positive breast cancers are considered prognostically more favorable than ER-negative tumors, whereas human epidermal growth factor receptor (HER)2/neu-positive breast cancers are associated with worse prognosis. The objective of the present study was to determine whether ER-positive and ER-negative status relates to epigenetic changes in breast cancer-related genes. To evaluate epigenetic differences in tumor-related genes relating to ER and HER2/neu status of primary tumors, we examined the promoter methylation status of the promoter region CpG islands of eight major breast tumor-related genes (RASSF1A, CCND2, GSPT1, TWIST, APC, NES1, RARβ2, and CDH1).

Methods

Paired ER-positive (n = 65) and ER-negative (n = 65) primary breast tumors (n = 130) matched for prognostic factors were assessed. DNA was extracted from paraffin-embedded tumor tissue after microdissection, and methylation-specific PCR and capillary-array electrophoresis analysis were performed.

Results

In early stages of tumor progression (T1 and N0), RASSF1A and CCND2 were significantly (P < 0.05) more methylated in ER-positive than in ER-negative tumors. GSTP1 hypermethylation was more frequent in the lymph node metastasis positive group than in the negative group. Double negative (ER-negative, HER2/neu-negative) breast cancers had significantly lesser frequencies of RASSF1A, GSTP1, and APC methylation (P < 0.0001, P < 0.0001, and P = 0.0035, respectively). Both ER and HER2/neu status correlated independently with these epigenetic alterations.

Conclusion

We demonstrated significant differences in tumor-related gene methylation patterns relevant to ER and HER2/neu status of breast tumors. This may be of significance in the assessment of targeted therapy resistance related to ER and HER2/neu status in breast cancer patients.