Uncovering genetic variations in HTR2A and miRNAs drivers of breast cancer risk in African American women.

Abstract

Background/objectives: Triple-negative breast cancer (TNBC) disproportionately affects African American (AA) women, yet the molecular mechanisms remain poorly understood. Emerging evidence suggests that microRNAs (miRNAs) may play a critical role in cancer progression. This study investigated the association of HTR2A genetic variants and miRNA dysregulation in AA women with breast cancer.

Methods: A total of 417 AA women (192 with breast cancer, 225 controls) were genotyped for selected HTR2A SNPs. Functional predictions and molecular modeling assessed structural impact. TNBC cell lines were treated with an HTR2A agonist, and miRNA expression was profiled using the NanoString, and bioinformatic tools were applied to identify miRNA targets and associated oncogenic pathways.

Results: Three SNPs (rs6304, rs6311, and rs1745837) were significantly associated with breast cancer risk (e.g., rs6311 dominant model: OR = 11.98, 95% CI: 6.63-21.66, p < 0.0001). The rs6304 demonstrated predicted protein destabilization. Six oncogenic miRNAs (including miR-92a-3p and miR-377-3p) were significantly upregulated (p < 0.05) and involved in PI3K/AKT, JAK/STAT, and IL-6 pathways.

Conclusions: HTR2A genetic variation, miRNA dysregulation, and increased breast cancer risk in AA women. These findings suggest that HTR2A variants and miRNA profiles may serve as potential biomarkers for risk stratification and targeted therapeutic approaches in TNBC.

Simple summary: African American women face a higher risk of developing a particularly aggressive type of breast cancer called TNBC. This study explores how changes in a specific serotonin receptor gene, known as HTR2A, might contribute to this risk. By analyzing the DNA of AA women and conducting lab experiments, the researchers identified genetic variations that are more common in women with breast cancer. They also discovered that these genetic changes may affect the way small molecules called microRNAs control cell growth. Understanding these links may help scientists find better ways to detect and treat breast cancer in AA women, paving the way for more personalized and effective medical care.