Identification of metabolic pathways contributing to ER+ breast cancer disparities using a machine-learning pipeline

Abstract

African American (AA) women in the United States have a 40% higher breast cancer mortality rate than Non-Hispanic White (NHW) women. The survival disparity is particularly striking among (estrogen receptor positive) ER+ breast cancer cases. The purpose of this study is to examine whether there are racial differences in metabolic pathways typically activated in patients with ER+ breast cancer. We collected pretreatment plasma from AA and NHW ER+ breast cancer cases (AA n = 48, NHW n = 54) and cancer-free controls (AA n = 100, NHW n = 48) to conduct an untargeted metabolomics analysis using gas chromatography mass spectrometry (GC–MS) to identify metabolites that may be altered in the different racial groups. Unpaired t-test combined with multiple feature selection and prediction models were employed to identify race-specific altered metabolic signatures. This was followed by the identification of altered metabolic pathways with a focus in AA patients with breast cancer. The clinical relevance of the identified pathways was further examined in PanCancer Atlas breast cancer data set from The Cancer Genome Atlas Program (TCGA). We identified differential metabolic signatures between NHW and AA patients. In AA patients, we observed decreased circulating levels of amino acids compared to healthy controls, while fatty acids were significantly higher in NHW patients. By mapping these metabolites to potential epigenetic regulatory mechanisms, this study identified significant associations with regulators of metabolism such as methionine adenosyltransferase 1A (MAT1A), DNA Methyltransferases and Histone methyltransferases for AA individuals, and Fatty acid Synthase (FASN) and Monoacylglycerol lipase (MGL) for NHW individuals. Specific gene Negative Elongation Factor Complex E (NELFE) with histone methyltransferase activity, was associated with poor survival exclusively for AA individuals. We employed a comprehensive and novel approach that integrates multiple machine learning and statistical methods, coupled with human functional pathway analyses. The metabolic profile of plasma samples identified may help elucidate underlying molecular drivers of disproportionately aggressive ER+ tumor biology in AA women. It may ultimately lead to the identification of novel therapeutic targets. To our knowledge, this is a novel finding that describes a link between metabolic alterations and epigenetic regulation in AA breast cancer and underscores the need for detailed investigations into the biological underpinnings of breast cancer health disparities.

Predictive analysis of breast cancer response to neoadjuvant chemotherapy through plasma metabolomics

“…The metabolic pathway involving glycine, serine, and threonine has been associated with breast cancer invasion [34] and may serve as a predictor for the response to neoadjuvant chemotherapy, particularly in triple-negative breast cancer [25]. Furthermore, serum threonine levels have shown signi cant variance in relation to responses to neoadjuvant chemotherapy in breast cancer patients [33], and plasma methionine levels were reported to be lower in ER-positive breast cancer patients compared to a healthy control group [35]. Hydroxyproline, a non-essential amino acid integral to collagen, has been noted for its altered levels in colorectal cancer [36].…”

Biological Basis of Breast Cancer-Related Disparities in Precision Oncology Era

“…Generally, African American (AA)/Black individuals are known to possess a significantly greater cancer burden, with the poorest likelihood of survival leading to the worst incidence of death of any race with regard to various types of cancer [34]. Consequently, AA women (AAW)/Black women have a 41% higher mortality rate compared to White women/non-Hispanic White (NHW) women [34,35]. For BC, racial disparities are accentuated in Black women, who have a lower incidence than White and Asian women, while their BC-related mortality and aggressiveness are the highest among all races [36].…”

“…Furthermore, even if the known risk variables do not entirely account for racial/ethnic variations in risk, the same authors demonstrated that relationships between obesity and oral contraceptive (OC) use with ER+ and ER− BCR differ by race/ethnicity [58]. The disparities are also particularly pronounced in ER+ BC patients, with AAW with ER+ subtype of BC experiencing four-five times higher mortality rates than their white counterparts [35].…”

The Role of Amino Acids in the Diagnosis, Risk Assessment, and Treatment of Breast Cancer: A Review

“…Santaliz Casiano et al found that amino acid levels are significantly lower in AA breast cancer patients than in healthy individuals [ 59 ]. The pathways associated with energy metabolism are glycolysis, amino acid metabolism, and the TCA cycle, which dominate in AA women with ER+ tumors, potentially indicating the aggressiveness of their tumors [ 76 ].…”