Metabolomic Transmethylation Profiling Reveals Differences in ER- Compared to ER+ Breast Cancer in African-American Women
Ashwini K Esnakula, Tammey J Naab, Luisel J Ricks-Santi, Sylvia Dasi, Henry Paul, Robert L DeWitty, Wayne Frederick, Edward Gabrielson, Yasmine M Kannan. Howard University Hospital, Washington, DC; Johns Hopkins University, Baltimore, MD
Background: Estrogen receptor negative (ER-) breast cancer, which is associated with poorer survival, is more common in younger African-American women when compared to other ethnic groups. The mechanisms, underlying these health disparities, remain largely unknown, especially in ER- breast cancer, which is often refractory to conventional therapy. Increased gene methylation frequency has been previously described in aggressive ER- breast cancer in African-American women. The goal of this study is to establish metabolomic transmethylation profiles in ER- and ER+ breast cancers from African-American women.
Design: Breast cancer tumor tissue methanol extracts from 15 ER- and 15 ER+ African-American women and several technical replicate samples from a homogenous pool containing a small amount of all study samples were analyzed using liquid/gas-chromatography coupled to mass spectrometry. Transmethylation pathway components were analyzed. Following log transformation and imputation with minimal observed values for each compound, Welch's two-sample t-test was used to identify metabolites that differed significantly between experimental groups.
Results: ER- breast cancer tumors showed significantly increased levels of methionine, S-adenosylhomocysteine and homocysteine when compared to ER+ tumors (p≤ 0.05), reflecting an increase in methionine accumulation and metabolism. Dimethylglycine and choline, intermediate metabolites, along with betaine, sarcosine and glycine were all collectively increased in the transmethylation pathway in the ER- cohort (p≤0.05). Two oncometabolites, sarcosine and 2-hydroxyglutamate were also elevated in ER- tumors (0.05<p<0.1). Hypermethylation in the ER- samples were further supported by increased concentrations of 4-methylglutamate, 2-methylbutyroylcarnitine, dimethylarginine, N1-methyladenosine, N1-methylguanosine, 5-methyluridine, N2,N2-dimethylguanosine, methyl-alpha-glucopyranoside, 5-methylthioadenosine and methylphosphate.
Conclusions: Our studies indicate that increased components of the transmethylation pathway observed in the ER- breast cancer samples could play an important role in the aggressiveness of ER- breast cancers. Metabolomics could help to identify novel therapeutic targets and biomarkers of diagnostic and prognostic significance.
Wednesday, March 21, 2012 9:30 AM
Poster Session V # 56, Wednesday Morning