mTOR pathway gene expression in association with race and clinicopathological characteristics in Black and White breast cancer patients

Abstract

Background Aberrant activation of the mammalian Target of Rapamycin (mTOR) pathway has been linked to obesity and endocrine therapy resistance, factors that may contribute to Black-White disparities in breast cancer outcomes. We evaluated associations of race and clinicopathological characteristics with mRNA expression of key mTOR pathway genes in breast tumors. Methods Surgical tumor tissue blocks were collected from 367 newly diagnosed breast cancer patients (190 Black and 177 White). Gene expression of AKT1, EIF4EBP1, MTOR, RPS6KB2, and TSC1 were quantified by NanoString nCounter. Differential gene expression was assessed using linear regression on log2-transformed values. Gene expression and DNA methylation data from TCGA were used for validation and investigation of race-related differences. Results Compared to White women, Black women had relative under-expression of AKT1 (log2 fold-change = − 0.31, 95% CI − 0.44, − 0.18) and RPS6KB2 (log2 fold-change = − 0.11, 95% CI − 0.19, − 0.03). Higher vs. lower tumor grade was associated with relative over-expression of EIF4EBP1 and RPS6KB2, but with lower expression of TSC1. Compared to luminal tumors, triple-negative tumors had relative under-expression of TSC1 (log2 fold-change = − 0.42, 95% CI − 0.22, − 0.01). The results were similar in the TCGA breast cancer dataset. Post-hoc analyses identified differential CpG methylation within the AKT1 and RPS6KB2 locus between Black and White women. Conclusions Over-expression of RPS6KB2 and EIF4EBP1 and under-expression of TSC1 might be indicators of more aggressive breast cancer phenotypes. Differential expression of AKT1 and RPS6KB2 by race warrants further investigation to elucidate their roles in racial disparities of treatment resistance and outcomes between Black and White women with breast cancer.

Network Pharmacology-Integrated Molecular Docking Reveals the Expected Anticancer Mechanism of Picrorhizae Rhizoma Extract

“…PPARG is a target associated with breast cancer, lung cancer, hypopharyngeal squamous cell carcinoma, esophageal carcinoma, and lung squamous cell carcinoma [38][39][40][41]. PTGS2 is a target associated with cervical cancer, pancreatic ductal adenocarcinoma, nasopharyngeal carcinoma, and colorectal cancer [42][43][44][45]. MTOR [45][46][47][48][49][50][51][52] is a target associated with breast cancer, bladder cancer, hysteromyoma, laryngeal cancer, kidney cancer, liver cancer, thy-roid cancer, epidermoid squamous cell carcinoma, and colorectal cancer.…”

The Interrelationship between Obesity and Race in Breast Cancer Prognosis: A Prospective Cohort Study

“…Previous works highlight the interaction between race and obesity at the molecular level; epigenetic modulation of multiple tumorigenic molecular pathways in adipocytes has been linked to differences in allcause mortality, progression, and metastasis in Black women compared to White women. [16,[18][19][20][21]28] The lack of independent association of obesity with PFS or OS may also be attributed to the limitations of BMI as a measure of obesity. Emerging evidence suggests that BMI is an oversimpli ed metric, as it does not distinguish between muscle and adipose, nor does it describe patterns of adipose distribution.…”

“…[13,16] Multiple studies have identi ed differences in the expression of cancer-associated genes in Black women compared to White women. [17][18][19] Because gene expression can be altered by environmental and/or lifestyle factors, epigenetic in uences may mediate the link between non-biological factors such as race or obesity, and the biological factors associated with worse breast cancer prognosis.…”

The interrelationship between obesity and race in breast cancer prognosis: a prospective cohort study

“…Biological factors underlying racial differences in outcomes include differences in the tumor microenvironment, gene expression, tumor suppressors, and genetic susceptibility loci [ 13 , 16 ]. Multiple studies have identified differences in the expression of cancer-associated genes in Black women compared to White women [ 17 – 19 ]. Because gene expression can be altered by environmental and/or lifestyle factors, epigenetic influences may mediate the link between non-biological factors such as race or obesity, and the biological factors associated with worse breast cancer prognosis.…”